rs369467132

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_017617.5(NOTCH1):​c.4828G>T​(p.Ala1610Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,582,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

NOTCH1
NM_017617.5 missense

Scores

1
18

Clinical Significance

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

Conservation

PhyloP100: 0.0800
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.

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=0.06837532).
BP6
Variant 9-136504863-C-A is Benign according to our data. Variant chr9-136504863-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241143.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH1NM_017617.5 linkuse as main transcriptc.4828G>T p.Ala1610Ser missense_variant 26/34 ENST00000651671.1 NP_060087.3
NOTCH1XM_011518717.3 linkuse as main transcriptc.4105G>T p.Ala1369Ser 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.4828G>T p.Ala1610Ser missense_variant 26/34 NM_017617.5 ENSP00000498587 P1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000314
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000101
AC:
2
AN:
197694
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
106940
show subpopulations
Gnomad AFR exome
AF:
0.0000876
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000675
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000280
AC:
4
AN:
1430416
Hom.:
0
Cov.:
33
AF XY:
0.00000282
AC XY:
2
AN XY:
708544
show subpopulations
Gnomad4 AFR exome
AF:
0.0000907
Gnomad4 AMR exome
AF:
0.00
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:
9.12e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.000314
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000232
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000837
AC:
1

ClinVar

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

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2022The p.A1610S variant (also known as c.4828G>T), located in coding exon 26 of the NOTCH1 gene, results from a G to T substitution at nucleotide position 4828. The alanine at codon 1610 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Adams-Oliver syndrome 5 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
15
DANN
Benign
0.70
DEOGEN2
Benign
0.31
T
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.41
T
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.068
T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.41
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.13
N
REVEL
Benign
0.21
Sift
Benign
0.73
T
Sift4G
Benign
0.73
T
Polyphen
0.0020
B
Vest4
0.13
MVP
0.51
MPC
0.76
ClinPred
0.049
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.17

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: rs369467132; hg19: chr9-139399315; API