Variant chr19-15181002-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BS2

The ENST00000263388.7(NOTCH3):c.2953C>G(p.Arg985Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,445,532 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R985C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NOTCH3
ENST00000263388.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.36

Variant links:

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

NOTCH3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 4 uncertain in ENST00000263388.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-15181002-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.2953C>G	p.Arg985Gly	missense_variant	18/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.2797C>G	p.Arg933Gly	missense_variant	17/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.2953C>G	p.Arg985Gly	missense_variant	18/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.2794C>G	p.Arg932Gly	missense_variant	17/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000464

AC:

AN:

215298

Hom.:

AF XY:

0.00

AC XY:

AN XY:

117598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1445532

Hom.:

Cov.:

AF XY:

0.00000836

AC XY:

AN XY:

717856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000190

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000626

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.62

T;T

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

0.81

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-4.1

D;.

REVEL

Uncertain

0.48

Sift

Benign

0.030

D;.

Sift4G

Benign

0.069

T;D

Polyphen

0.76

P;.

Vest4

0.56

MutPred

0.73

Loss of disorder (P = 0.2222);.;

MVP

0.98

MPC

0.60

ClinPred

0.67

GERP RS

1.6

Varity_R

0.36

gMVP

0.80

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over