9-136506633-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017617.5(NOTCH1):​c.3908G>A​(p.Arg1303His) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,606,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.69
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21988884).
BS2
High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOTCH1NM_017617.5 linkc.3908G>A p.Arg1303His missense_variant Exon 24 of 34 ENST00000651671.1 NP_060087.3 P46531
NOTCH1XM_011518717.3 linkc.3185G>A p.Arg1062His missense_variant Exon 21 of 31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkc.3908G>A p.Arg1303His missense_variant Exon 24 of 34 NM_017617.5 ENSP00000498587.1 P46531

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD3 exomes
AF:
0.0000640
AC:
15
AN:
234226
Hom.:
0
AF XY:
0.0000470
AC XY:
6
AN XY:
127580
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000392
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000509
Gnomad NFE exome
AF:
0.00000946
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000131
AC:
19
AN:
1454574
Hom.:
0
Cov.:
34
AF XY:
0.0000111
AC XY:
8
AN XY:
722976
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000320
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000361
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000499
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Jul 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R1303H variant (also known as c.3908G>A), located in coding exon 24 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 3908. The arginine at codon 1303 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is 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 variant remains unclear. -

Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 Uncertain:1
-
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NOTCH1 NM_017617 exon24 p.Arg1303His (c.3908G>A): This variant has not been reported in the literature but is present in 14/33164 Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs768775024). Computational predictive tools suggest that this variant may not impact the protein. Of note, 5 other species carry a histidine (His) at this position, further suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1
Oct 17, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NOTCH1 c.3908G>A; p.Arg1303His variant (rs768775024), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 477924). This variant is found in the general population with an overall allele frequency of 0.0060% (16/265526 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.323). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Adams-Oliver syndrome 5 Benign:1
Nov 11, 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
0.094
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
23
DANN
Benign
0.81
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.090
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.22
T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
-0.32
N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
1.0
N
REVEL
Uncertain
0.32
Sift
Benign
0.88
T
Sift4G
Benign
0.79
T
Polyphen
0.057
B
Vest4
0.39
MutPred
0.72
Loss of MoRF binding (P = 0.0607);
MVP
0.68
MPC
0.55
ClinPred
0.062
T
GERP RS
4.6
Varity_R
0.097

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs768775024; hg19: chr9-139401085; API