rs140040122

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000263388.7(NOTCH3):c.2202C>T(p.Ala734=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,612,552 control chromosomes in the GnomAD database, including 8 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 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 8 hom. )

Consequence

NOTCH3
ENST00000263388.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.361

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-15185351-G-A is Benign according to our data. Variant chr19-15185351-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15185351-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.361 with no splicing effect.

BS2

High AC in GnomAd4 at 375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.2202C>T	p.Ala734=	synonymous_variant	14/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5 linkuse as main transcript	c.2202C>T	p.Ala734=	synonymous_variant	14/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.2202C>T	p.Ala734=	synonymous_variant	14/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.2199C>T	p.Ala733=	synonymous_variant	14/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

376

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000823

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00390

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00210

AC:

516

AN:

245730

Hom.:

AF XY:

0.00225

AC XY:

302

AN XY:

134046

show subpopulations

Gnomad AFR exome

AF:

0.000850

Gnomad AMR exome

AF:

0.00140

Gnomad ASJ exome

AF:

0.00202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00164

Gnomad FIN exome

AF:

0.00127

Gnomad NFE exome

AF:

0.00308

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00315

AC:

4597

AN:

1460540

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2206

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00206

Gnomad4 NFE exome

AF:

0.00360

Gnomad4 OTH exome

AF:

0.00305

GnomAD4 genome

AF:

0.00247

AC:

375

AN:

152012

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

164

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000820

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00389

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00276

Hom.:

Bravo

AF:

0.00234

EpiCase

AF:

0.00305

EpiControl

AF:

0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2023	- -
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	Jul 01, 2024	NOTCH3: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

Aug 31, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.7

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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