Variant 19-15185632-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_ModerateBS2

The NM_000435.3(NOTCH3):c.1999G>A(p.Gly667Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. G667C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.73

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 Likely_benign. Variant got -4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-15185632-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447805.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.13681626).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.1999G>A	p.Gly667Ser	missense_variant	13/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.1999G>A	p.Gly667Ser	missense_variant	13/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.1999G>A	p.Gly667Ser	missense_variant	13/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.1996G>A	p.Gly666Ser	missense_variant	13/23	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250816

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

-0.65

N;.

MutationTaster

Benign

0.56

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.89

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.48

T;.

Sift4G

Benign

0.55

T;T

Polyphen

0.12

B;.

Vest4

0.39

MVP

0.97

MPC

0.46

ClinPred

0.074

GERP RS

4.0

Varity_R

0.049

gMVP

0.54

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