rs1044008

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000435.3(NOTCH3):c.6438G>A(p.Ala2146Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,539,680 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 111 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1220 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-15161190-C-T is Benign according to our data. Variant chr19-15161190-C-T is described in ClinVar as [Benign]. Clinvar id is 256151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15161190-C-T is described in Lovd as [Benign]. Variant chr19-15161190-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.73 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0311 (4732/152282) while in subpopulation NFE AF= 0.043 (2926/67996). AF 95% confidence interval is 0.0417. There are 111 homozygotes in gnomad4. There are 2366 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4732 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.6438G>A	p.Ala2146Ala	synonymous_variant	Exon 33 of 33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 link	c.6282G>A	p.Ala2094Ala	synonymous_variant	Exon 32 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.6438G>A	p.Ala2146Ala	synonymous_variant	Exon 33 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4733

AN:

152164

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00777

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0369

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0134

Gnomad FIN

AF:

0.0543

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0430

Gnomad OTH

AF:

0.0373

GnomAD3 exomes

AF:

0.0319

AC:

4332

AN:

135802

Hom.:

AF XY:

0.0308

AC XY:

2285

AN XY:

74102

show subpopulations

Gnomad AFR exome

AF:

0.00608

Gnomad AMR exome

AF:

0.0411

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.00178

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.0549

Gnomad NFE exome

AF:

0.0427

Gnomad OTH exome

AF:

0.0351

GnomAD4 exome

AF:

0.0397

AC:

55073

AN:

1387398

Hom.:

1220

Cov.:

AF XY:

0.0391

AC XY:

26792

AN XY:

684784

show subpopulations

Gnomad4 AFR exome

AF:

0.00641

Gnomad4 AMR exome

AF:

0.0408

Gnomad4 ASJ exome

AF:

0.0348

Gnomad4 EAS exome

AF:

0.000686

Gnomad4 SAS exome

AF:

0.0141

Gnomad4 FIN exome

AF:

0.0570

Gnomad4 NFE exome

AF:

0.0435

Gnomad4 OTH exome

AF:

0.0361

GnomAD4 genome

AF:

0.0311

AC:

4732

AN:

152282

Hom.:

111

Cov.:

AF XY:

0.0318

AC XY:

2366

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00775

Gnomad4 AMR

AF:

0.0368

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.0135

Gnomad4 FIN

AF:

0.0543

Gnomad4 NFE

AF:

0.0430

Gnomad4 OTH

AF:

0.0369

Alfa

AF:

0.0388

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.14

DANN

Benign

0.25

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