19-15174252-G-T

Position:

chr19-15174252-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000435.3(NOTCH3):c.4552C>A(p.Leu1518Met) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,585,906 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 19 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.81

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011193216).

BP6

Variant 19-15174252-G-T is Benign according to our data. Variant chr19-15174252-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15174252-G-T is described in Lovd as [Benign]. Variant chr19-15174252-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00248 (378/152366) while in subpopulation EAS AF= 0.00829 (43/5184). AF 95% confidence interval is 0.00633. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.4552C>A	p.Leu1518Met	missense_variant	25/33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 linkuse as main transcript	c.4396C>A	p.Leu1466Met	missense_variant	24/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.4552C>A	p.Leu1518Met	missense_variant	25/33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00371

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00828

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00466

AC:

910

AN:

195106

Hom.:

AF XY:

0.00401

AC XY:

431

AN XY:

107508

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.0186

Gnomad ASJ exome

AF:

0.00463

Gnomad EAS exome

AF:

0.00687

Gnomad SAS exome

AF:

0.00437

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000482

Gnomad OTH exome

AF:

0.00467

GnomAD4 exome

AF:

0.00147

AC:

2112

AN:

1433540

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1075

AN XY:

711922

show subpopulations

Gnomad4 AFR exome

AF:

0.00429

Gnomad4 AMR exome

AF:

0.0163

Gnomad4 ASJ exome

AF:

0.00354

Gnomad4 EAS exome

AF:

0.00951

Gnomad4 SAS exome

AF:

0.00449

Gnomad4 FIN exome

AF:

0.0000215

Gnomad4 NFE exome

AF:

0.000219

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152366

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

197

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00373

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00829

Gnomad4 SAS

AF:

0.00579

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.00346

ESP6500AA

AF:

0.00301

AC:

ESP6500EA

AF:

0.000591

AC:

ExAC

AF:

0.00317

AC:

375

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	This variant is associated with the following publications: (PMID: 30054184, 22006983) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	NOTCH3: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.28

MVP

0.85

MPC

2.6

ClinPred

0.016

GERP RS

4.8

Varity_R

0.69

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over