chr19-15159725-A-G

Variant names:

• chr19-15159725-A-G
• rs16980378
• NM_000435.3:c.*937T>C

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.*937T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 233,160 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (29 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.134

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=-0.59).
• BP6: Variant 19-15159725-A-G is Benign according to our data. Variant chr19-15159725-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 328356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.*937T>C		3_prime_UTR_variant	Exon 33 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.*937T>C		3_prime_UTR_variant	Exon 32 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388	c.*937T>C		3_prime_UTR_variant	Exon 33 of 33	1	NM_000435.3	ENSP00000263388.1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152246 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.0117 AC: 944 AN: 80796 Hom.: 29 Cov.: 0 AF XY: 0.0118 AC XY: 439 AN XY: 37128

Gnomad4 AFR exome AF: 0.000772

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.00254

Gnomad4 EAS exome AF: 0.0729

Gnomad4 SAS exome AF: 0.00426

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000100

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00310 AC: 473 AN: 152364 Hom.: 7 Cov.: 32 AF XY: 0.00369 AC XY: 275 AN XY: 74516

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0352

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.00455

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Likely 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.78

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: rs16980378; hg19: chr19-15270536;