19-15179196-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000435.3(NOTCH3):c.3547G>A(p.Val1183Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,932 control chromosomes in the GnomAD database, including 2,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 1277 hom., cov: 34)

Exomes 𝑓: 0.013 ( 1237 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.97

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:

MIR6795 (HGNC:50031): (microRNA 6795) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6795 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024884641).

BP6

Variant 19-15179196-C-T is Benign according to our data. Variant chr19-15179196-C-T is described in ClinVar as [Benign]. Clinvar id is 256133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15179196-C-T is described in Lovd as [Benign]. Variant chr19-15179196-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.3547G>A	p.Val1183Met	missense_variant	Exon 22 of 33	ENST00000263388.7	NP_000426.2	Q9UM47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.3547G>A	p.Val1183Met	missense_variant	Exon 22 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.0760

AC:

11553

AN:

152090

Hom.:

1271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0291

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00646

Gnomad OTH

AF:

0.0541

GnomAD3 exomes

AF:

0.0253

AC:

6341

AN:

250230

Hom.:

536

AF XY:

0.0218

AC XY:

2948

AN XY:

135474

show subpopulations

Gnomad AFR exome

AF:

0.253

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0266

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0211

Gnomad FIN exome

AF:

0.00233

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.0175

GnomAD4 exome

AF:

0.0135

AC:

19696

AN:

1461722

Hom.:

1237

Cov.:

AF XY:

0.0130

AC XY:

9469

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.251

Gnomad4 AMR exome

AF:

0.0164

Gnomad4 ASJ exome

AF:

0.0261

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0219

Gnomad4 FIN exome

AF:

0.00223

Gnomad4 NFE exome

AF:

0.00565

Gnomad4 OTH exome

AF:

0.0236

GnomAD4 genome

AF:

0.0760

AC:

11570

AN:

152210

Hom.:

1277

Cov.:

AF XY:

0.0729

AC XY:

5425

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.247

Gnomad4 AMR

AF:

0.0290

Gnomad4 ASJ

AF:

0.0256

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0184

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00646

Gnomad4 OTH

AF:

0.0535

Alfa

AF:

0.0207

Hom.:

412

Bravo

AF:

0.0859

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.242

AC:

1066

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.0297

AC:

3608

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00557

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30530974, 29544907) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 02, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;D

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.5

N;.

REVEL

Uncertain

0.64

Sift

Benign

0.035

D;.

Sift4G

Uncertain

0.017

D;D

Polyphen

0.70

P;.

Vest4

0.14

MPC

0.73

ClinPred

0.013

GERP RS

3.9

Varity_R

0.19

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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