chr19-15159772-G-A

Position:

• chr19-15159772-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.*890C>T 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 233,184 control chromosomes in the GnomAD database, including 57,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36426 hom., cov: 34)
  • Exomes 𝑓: 0.72 (21187 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.668

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 19-15159772-G-A is Benign according to our data. Variant chr19-15159772-G-A is described in ClinVar as [Benign]. Clinvar id is 328357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.*890C>T		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.*890C>T		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.*890C>T		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103911 AN: 152020 Hom.: 36417 Cov.: 34

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: 0.805

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.683

GnomAD4 exome AF: 0.718 AC: 58204 AN: 81046 Hom.: 21187 Cov.: 0 AF XY: 0.723 AC XY: 26969 AN XY: 37280

Gnomad4 AFR exome AF: 0.520

Gnomad4 AMR exome AF: 0.587

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.617

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.793

Gnomad4 NFE exome AF: 0.764

Gnomad4 OTH exome AF: 0.696

GnomAD4 genome AF: 0.683 AC: 103946 AN: 152138 Hom.: 36426 Cov.: 34 AF XY: 0.683 AC XY: 50820 AN XY: 74380

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.726

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.805

Gnomad4 NFE AF: 0.772

Gnomad4 OTH AF: 0.684

Alfa AF: 0.747 Hom.: 69945

Bravo AF: 0.659

Asia WGS AF: 0.638 AC: 2220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.5
DANN	Benign	0.85

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: rs1044123; hg19: chr19-15270583;