chr9-136514609-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_017617.5(NOTCH1):c.2108G>A(p.Arg703His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000839 in 1,609,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R703C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2O:1

Conservation

PhyloP100: 0.747

Publications

9 publications found

Variant links:

COSMIC-nc: COSV99077670

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 Gene-Disease associations (from GenCC):

Adams-Oliver syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
Adams-Oliver syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
aortic valve disease 1
Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
connective tissue disorder
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leukodystrophy
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
familial bicuspid aortic valve
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

NOTCH1 links:

LOC124902310 (HGNC:):

LOC124902310 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14821985).

BP6

Variant 9-136514609-C-T is Benign according to our data. Variant chr9-136514609-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134912.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000591 (9/152298) while in subpopulation SAS AF = 0.000828 (4/4830). AF 95% confidence interval is 0.000282. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5 link	c.2108G>A	p.Arg703His	missense_variant	Exon 13 of 34	ENST00000651671.1	NP_060087.3	P46531
NOTCH1	XM_011518717.3 link	c.1385G>A	p.Arg462His	missense_variant	Exon 10 of 31		XP_011517019.2
LOC124902310	XR_007061865.1 link	n.507+4630C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1 link	c.2108G>A	p.Arg703His	missense_variant	Exon 13 of 34		NM_017617.5	ENSP00000498587.1		P46531

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000117

AC:

AN:

238950

AF XY:

0.000138

show subpopulations

Gnomad AFR exome

AF:

0.0000703

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000648

Gnomad OTH exome

AF:

0.000869

GnomAD4 exome

AF:

0.0000865

AC:

126

AN:

1456978

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

724560

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33456

American (AMR)

AF:

0.0000678

AC:

AN:

44266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39564

South Asian (SAS)

AF:

0.000654

AC:

AN:

85624

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51366

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000396

AC:

AN:

1110798

Other (OTH)

AF:

0.000183

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41554

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000133

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NOTCH1 p.Arg703His variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs561126575), ClinVar (classified as uncertain significance by Ambry Genetics and Invitae; associated conditions are Adams-Oliver syndrome 5 and cardiovascular phenotype), and in Cosmic (FATHMM prediction of Pathogenic; score 0.75). The variant was also identified in control databases in 28 of 238950 chromosomes at a frequency of 0.000117 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 14 of 29858 chromosomes (freq: 0.000469), Other in 5 of 5754 chromosomes (freq: 0.000869), Latino in 1 of 33802 chromosomes (freq: 0.00003), European (non-Finnish) in 7 of 108000 chromosomes (freq: 0.000065), and African in 1 of 14228 chromosomes (freq: 0.00007), while the variant was not observed in the European (Finnish), East Asian, and Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. The p.Arg703 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Mar 31, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

May 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NOTCH1 c.2108G>A (p.Arg703His) results in a non-conservative amino acid change located in the EGF like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 238950 control chromosomes. The observed variant frequency is approximately 190 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). To our knowledge, no occurrence of c.2108G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134912). Based on the evidence outlined above, the variant was classified as likely benign. -

NOTCH1-related disorder

Uncertain:1

Feb 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NOTCH1 c.2108G>A variant is predicted to result in the amino acid substitution p.Arg703His. To our knowledge, this variant has not been reported to be associated with disease in the literature. This variant is reported in 0.047% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Feb 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2108G>A (p.R703H) alteration is located in exon 13 (coding exon 13) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 2108, causing the arginine (R) at amino acid position 703 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Adams-Oliver syndrome 5

Benign:1

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.12

PhyloP100

0.75

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.61

REVEL

Benign

0.23

Sift

Benign

0.18

Sift4G

Benign

0.20

Polyphen

0.0040

Vest4

0.23

MVP

0.71

MPC

0.47

ClinPred

0.015

GERP RS

1.0

Varity_R

0.043

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over