19-15159825-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.*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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

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=-0.88).
• 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_single_submitter, 1 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	c.*837G>A		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.*837G>A		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	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.: 75 Cov.: 35

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.: 62 Cov.: 0 AF XY: 0.0343 AC XY: 1284 AN XY: 37448

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.: 75 Cov.: 35 AF XY: 0.0224 AC XY: 1670 AN XY: 74506

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.: 61

Bravo AF: 0.0216

Asia WGS AF: 0.0700 AC: 242 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

- -

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

Other links and lift over

dbSNP: rs12082; hg19: chr19-15270636;