Variant chr19-15159854-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.992

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_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 linkuse as main transcript	c.*808G>A		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.*808G>A		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	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.:

show subpopulations

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.:

AF XY:

0.723

AC XY:

27107

AN XY:

37472

show subpopulations

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.:

AF XY:

0.683

AC XY:

50849

AN XY:

74424

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

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

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