Variant 19-15159994-C-A 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.*668G>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 233,276 control chromosomes in the GnomAD database, including 57,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 36415 hom., cov: 33)

Exomes 𝑓: 0.72 ( 21184 hom. )

Consequence

NOTCH3
NM_000435.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.336

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 19-15159994-C-A is Benign according to our data. Variant chr19-15159994-C-A is described in ClinVar as [Benign]. Clinvar id is 328361.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.*668G>T		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.*668G>T		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.*668G>T		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes

AF:

0.683

AC:

103901

AN:

152030

Hom.:

36406

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:

0.578

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.806

Gnomad MID

AF:

0.680

Gnomad NFE

AF:

0.772

Gnomad OTH

AF:

0.683

GnomAD4 exome

AF:

0.718

AC:

58243

AN:

81128

Hom.:

21184

Cov.:

AF XY:

0.723

AC XY:

27008

AN XY:

37348

show subpopulations

Gnomad4 AFR exome

AF:

0.520

Gnomad4 AMR exome

AF:

0.589

Gnomad4 ASJ exome

AF:

0.737

Gnomad4 EAS exome

AF:

0.609

Gnomad4 SAS exome

AF:

0.743

Gnomad4 FIN exome

AF:

0.796

Gnomad4 NFE exome

AF:

0.765

Gnomad4 OTH exome

AF:

0.697

GnomAD4 genome

AF:

0.683

AC:

103936

AN:

152148

Hom.:

36415

Cov.:

AF XY:

0.683

AC XY:

50810

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.533

Gnomad4 AMR

AF:

0.616

Gnomad4 ASJ

AF:

0.726

Gnomad4 EAS

AF:

0.578

Gnomad4 SAS

AF:

0.722

Gnomad4 FIN

AF:

0.806

Gnomad4 NFE

AF:

0.772

Gnomad4 OTH

AF:

0.684

Alfa

AF:

0.678

Hom.:

2237

Bravo

AF:

0.659

Asia WGS

AF:

0.637

AC:

2218

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

-0.68

CADD

Benign

8.3

DANN

Benign

0.82

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