rs114207045

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP6_Very_StrongBS1BS2

The ENST00000263388.7(NOTCH3):c.1490C>T(p.Ser497Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00527 in 1,593,160 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S497W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0075 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 37 hom. )

Consequence

NOTCH3
ENST00000263388.7 missense, splice_region

Scores

Splicing: ADA: 0.9616

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.28

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in ENST00000263388.7

BP6

Variant 19-15188237-G-A is Benign according to our data. Variant chr19-15188237-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15188237-G-A is described in Lovd as [Benign]. Variant chr19-15188237-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00746 (1136/152180) while in subpopulation AMR AF= 0.0104 (159/15286). AF 95% confidence interval is 0.00908. There are 6 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	9/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	9/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	9/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.1487C>T	p.Ser496Leu	missense_variant, splice_region_variant	9/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes

AF:

0.00747

AC:

1136

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00971

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00496

Gnomad OTH

AF:

0.00959

GnomAD3 exomes

AF:

0.00669

AC:

1490

AN:

222722

Hom.:

AF XY:

0.00670

AC XY:

805

AN XY:

120082

show subpopulations

Gnomad AFR exome

AF:

0.00980

Gnomad AMR exome

AF:

0.00639

Gnomad ASJ exome

AF:

0.00691

Gnomad EAS exome

AF:

0.000466

Gnomad SAS exome

AF:

0.00727

Gnomad FIN exome

AF:

0.0138

Gnomad NFE exome

AF:

0.00554

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00504

AC:

7256

AN:

1440980

Hom.:

Cov.:

AF XY:

0.00515

AC XY:

3682

AN XY:

714970

show subpopulations

Gnomad4 AFR exome

AF:

0.00970

Gnomad4 AMR exome

AF:

0.00642

Gnomad4 ASJ exome

AF:

0.00682

Gnomad4 EAS exome

AF:

0.000306

Gnomad4 SAS exome

AF:

0.00625

Gnomad4 FIN exome

AF:

0.0131

Gnomad4 NFE exome

AF:

0.00433

Gnomad4 OTH exome

AF:

0.00724

GnomAD4 genome

AF:

0.00746

AC:

1136

AN:

152180

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

584

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00968

Gnomad4 AMR

AF:

0.0104

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00871

Gnomad4 FIN

AF:

0.0132

Gnomad4 NFE

AF:

0.00496

Gnomad4 OTH

AF:

0.00949

Alfa

AF:

0.00530

Hom.:

Bravo

AF:

0.00691

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00569

AC:

687

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NOTCH3: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.0081

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.8

D;.

REVEL

Benign

0.26

Sift

Benign

0.47

T;.

Sift4G

Benign

0.50

T;D

Polyphen

0.065

B;.

Vest4

0.31

MVP

0.99

MPC

0.42

ClinPred

0.021

GERP RS

5.0

Varity_R

0.15

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.76

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over