19-15192033-T-C

Position:

• chr19-15192033-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000435.3(NOTCH3):​c.606A>G​(p.Ala202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,613,208 control chromosomes in the GnomAD database, including 615,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57799 hom., cov: 34)
  • Exomes 𝑓: 0.87 (558124 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.47

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-15192033-T-C is Benign according to our data. Variant chr19-15192033-T-C is described in ClinVar as [Benign]. Clinvar id is 256148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15192033-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.606A>G	p.Ala202=	synonymous_variant	4/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.606A>G	p.Ala202=	synonymous_variant	4/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.606A>G	p.Ala202=	synonymous_variant	4/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1	c.603A>G	p.Ala201=	synonymous_variant	4/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132353 AN: 152104 Hom.: 57761 Cov.: 34

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.866

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.847

GnomAD3 exomes AF: 0.848 AC: 212142 AN: 250060 Hom.: 90518 AF XY: 0.851 AC XY: 115350 AN XY: 135582

Gnomad AFR exome AF: 0.909

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.871

Gnomad EAS exome AF: 0.863

Gnomad SAS exome AF: 0.840

Gnomad FIN exome AF: 0.866

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.845

GnomAD4 exome AF: 0.873 AC: 1275651 AN: 1460986 Hom.: 558124 Cov.: 84 AF XY: 0.872 AC XY: 633809 AN XY: 726822

Gnomad4 AFR exome AF: 0.908

Gnomad4 AMR exome AF: 0.708

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 0.880

Gnomad4 SAS exome AF: 0.841

Gnomad4 FIN exome AF: 0.866

Gnomad4 NFE exome AF: 0.882

Gnomad4 OTH exome AF: 0.860

GnomAD4 genome AF: 0.870 AC: 132443 AN: 152222 Hom.: 57799 Cov.: 34 AF XY: 0.867 AC XY: 64511 AN XY: 74416

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.763

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.866

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.863

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.844

Alfa AF: 0.881 Hom.: 31239

Bravo AF: 0.865

Asia WGS AF: 0.837 AC: 2908 AN: 3478

EpiCase AF: 0.872

EpiControl AF: 0.867

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

Lateral meningocele syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.18

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

Other links and lift over

dbSNP: rs1043994; hg19: chr19-15302844;