rs1044116

chr19-15159854-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000435.3(NOTCH3):c.*808G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 233,580 control chromosomes in the GnomAD database, including 57,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (36445 hom., cov: 35)
  • Exomes 𝑓: 0.72 (21271 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.992

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-15159854-C-T is Benign according to our data. Variant chr19-15159854-C-T is described in ClinVar as [Benign]. Clinvar id is 328360.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.*808G>A		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.*808G>A		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.*808G>A		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103964 AN: 152108 Hom.: 36436 Cov.: 35

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.718 AC: 58432 AN: 81354 Hom.: 21271 Cov.: 0 AF XY: 0.723 AC XY: 27107 AN XY: 37472

Gnomad4 AFR exome AF: 0.521

Gnomad4 AMR exome AF: 0.588

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.617

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.794

Gnomad4 NFE exome AF: 0.764

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.683 AC: 103999 AN: 152226 Hom.: 36445 Cov.: 35 AF XY: 0.683 AC XY: 50849 AN XY: 74424

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.615

Gnomad4 ASJ AF: 0.726

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.806

Gnomad4 NFE AF: 0.772

Gnomad4 OTH AF: 0.684

Alfa AF: 0.739 Hom.: 40618

Bravo AF: 0.659

Asia WGS AF: 0.639 AC: 2222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.5
Dann	Benign	0.65

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: rs1044116; hg19: chr19-15270665; COSMIC: COSV54633741; COSMIC: COSV54633741;