9-136523737-C-T

Variant names:

• chr9-136523737-C-T
• rs754086897
• NM_017617.5:c.383G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_017617.5(NOTCH1):​c.383G>A​(p.Arg128His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,609,062 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. R128C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.38
• Publications: 8 publications found

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

LOC124902310 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22551471).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000177 (27/152334) while in subpopulation AFR AF = 0.000625 (26/41578). AF 95% confidence interval is 0.000438. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH1	NM_017617.5	c.383G>A	p.Arg128His	missense_variant	Exon 3 of 34	ENST00000651671.1	NP_060087.3
NOTCH1	XM_011518717.3	c.20-4172G>A		intron_variant	Intron 1 of 30		XP_011517019.2
LOC124902310	XR_007061865.1	n.623+304C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH1	ENST00000651671.1	c.383G>A	p.Arg128His	missense_variant	Exon 3 of 34		NM_017617.5	ENSP00000498587.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000753 AC: 18 AN: 239062 AF XY: 0.0000764

Gnomad AFR exome AF: 0.000696

Gnomad AMR exome AF: 0.0000591

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1456728 Hom.: 0 Cov.: 32 AF XY: 0.0000221 AC XY: 16 AN XY: 724466

African (AFR) AF: 0.000718 AC: 24 AN: 33420

American (AMR) AF: 0.0000676 AC: 3 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4852

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60094

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152334 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74488

African (AFR) AF: 0.000625 AC: 26 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.0000752 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Adams-Oliver syndrome 5 Uncertain:1 Benign:1

Feb 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R128H variant (also known as c.383G>A), located in coding exon 3 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 383. The arginine at codon 128 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Aug 16, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the NOTCH1 gene. The R128H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the R128H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where histidine is the wild type in several species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -

Aortic valve disease 1 Uncertain:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.53	N
PhyloP100		1.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.041	B
Vest4		0.22
MVP		0.74
MPC		0.49
ClinPred		0.017	T
GERP RS		2.3
Varity_R		0.073
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs754086897; hg19: chr9-139418189; COSMIC: COSV53084202;