rs16980398

Positions:

• chr19-15165928-A-G

Variant summary

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

The ENST00000263388.7(NOTCH3):​c.5526T>C​(p.Ala1842=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,614,030 control chromosomes in the GnomAD database, including 5,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (3033 hom., cov: 32)
  • Exomes 𝑓: 0.018 (2817 hom.)
• Consequence: NOTCH3 ENST00000263388.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.674

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=-0.64).
• BP6: Variant 19-15165928-A-G is Benign according to our data. Variant chr19-15165928-A-G is described in ClinVar as [Benign]. Clinvar id is 256144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15165928-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.674 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.5526T>C	p.Ala1842=	synonymous_variant	30/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.5370T>C	p.Ala1790=	synonymous_variant	29/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.5526T>C	p.Ala1842=	synonymous_variant	30/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000597756.1	c.42T>C	p.Ala14=	synonymous_variant	1/3	2		ENSP00000468879
NOTCH3	ENST00000595514.1	c.229-413T>C		intron_variant, NMD_transcript_variant		3		ENSP00000470661

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17321 AN: 152036 Hom.: 3018 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00704

Gnomad OTH AF: 0.0818

GnomAD3 exomes AF: 0.0352 AC: 8840 AN: 251236 Hom.: 1250 AF XY: 0.0288 AC XY: 3906 AN XY: 135822

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0212

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00669

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0176 AC: 25702 AN: 1461876 Hom.: 2817 Cov.: 34 AF XY: 0.0166 AC XY: 12067 AN XY: 727242

Gnomad4 AFR exome AF: 0.390

Gnomad4 AMR exome AF: 0.0221

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.00223

Gnomad4 NFE exome AF: 0.00618

Gnomad4 OTH exome AF: 0.0320

GnomAD4 genome AF: 0.114 AC: 17368 AN: 152154 Hom.: 3033 Cov.: 32 AF XY: 0.110 AC XY: 8153 AN XY: 74376

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.0414

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00704

Gnomad4 OTH AF: 0.0810

Alfa AF: 0.0270 Hom.: 1003

Bravo AF: 0.129

Asia WGS AF: 0.0240 AC: 86 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00652

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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	-	- -

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 12, 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	-0.64
CADD	Benign	8.7
DANN	Benign	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

Other links and lift over

dbSNP: rs16980398; hg19: chr19-15276739; COSMIC: COSV54642976;