Variant 19-15159825-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.*837G>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 0.0261 in 233,650 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 75 hom., cov: 35)

Exomes 𝑓: 0.034 ( 62 hom. )

Consequence

NOTCH3
NM_000435.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.18

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=-0.88).

BP6

Variant 19-15159825-C-T is Benign according to our data. Variant chr19-15159825-C-T is described in ClinVar as [Benign]. Clinvar id is 328359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0867 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.*837G>A		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5 linkuse as main transcript	c.*837G>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.*837G>A		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3372

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0932

Gnomad SAS

AF:

0.0525

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0201

GnomAD4 exome

AF:

0.0337

AC:

2739

AN:

81274

Hom.:

Cov.:

AF XY:

0.0343

AC XY:

1284

AN XY:

37448

show subpopulations

Gnomad4 AFR exome

AF:

0.00541

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.00939

Gnomad4 EAS exome

AF:

0.0804

Gnomad4 SAS exome

AF:

0.0370

Gnomad4 FIN exome

AF:

0.00617

Gnomad4 NFE exome

AF:

0.0295

Gnomad4 OTH exome

AF:

0.0287

GnomAD4 genome

AF:

0.0221

AC:

3367

AN:

152376

Hom.:

Cov.:

AF XY:

0.0224

AC XY:

1670

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00608

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.0936

Gnomad4 SAS

AF:

0.0519

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0283

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0269

Hom.:

Bravo

AF:

0.0216

Asia WGS

AF:

0.0700

AC:

242

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

- -

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

-0.88

CADD

Benign

2.8

DANN

Benign

0.48

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