rs372830543

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2

The NM_017617.5(NOTCH1):​c.5015G>A​(p.Arg1672His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,511,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

3
16

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 2.94
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 Benign. Variant got -7 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH1. . Trascript score misZ 3.6761 (greater than threshold 3.09). GenCC has associacion of gene with familial bicuspid aortic valve, familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome, connective tissue disorder, Adams-Oliver syndrome 5, aortic valve disease 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.2031466).
BP6
Variant 9-136504676-C-T is Benign according to our data. Variant chr9-136504676-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134941.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.5015G>A p.Arg1672His missense_variant 26/34 ENST00000651671.1 NP_060087.3
NOTCH1XM_011518717.3 linkuse as main transcriptc.4292G>A p.Arg1431His missense_variant 23/31 XP_011517019.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH1ENST00000651671.1 linkuse as main transcriptc.5015G>A p.Arg1672His missense_variant 26/34 NM_017617.5 ENSP00000498587 P1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000744
AC:
9
AN:
121020
Hom.:
0
AF XY:
0.0000466
AC XY:
3
AN XY:
64376
show subpopulations
Gnomad AFR exome
AF:
0.000157
Gnomad AMR exome
AF:
0.0000458
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000488
Gnomad SAS exome
AF:
0.0000581
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000228
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000235
AC:
32
AN:
1359570
Hom.:
0
Cov.:
33
AF XY:
0.0000240
AC XY:
16
AN XY:
665870
show subpopulations
Gnomad4 AFR exome
AF:
0.000358
Gnomad4 AMR exome
AF:
0.0000613
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000199
Gnomad4 SAS exome
AF:
0.0000676
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000472
Gnomad4 OTH exome
AF:
0.0000356
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000604
Hom.:
0
Bravo
AF:
0.000125
ESP6500AA
AF:
0.000657
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000139
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 02, 2023- -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.53
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.041
Sift
Benign
0.14
T
Sift4G
Benign
0.57
T
Polyphen
0.0060
B
Vest4
0.36
MVP
0.35
MPC
0.99
ClinPred
0.033
T
GERP RS
3.6
Varity_R
0.37

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: rs372830543; hg19: chr9-139399128; COSMIC: COSV53032959; API