19-15160099-A-G

Variant names:

• chr19-15160099-A-G
• rs77669983
• NM_000435.3:c.*563T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.*563T>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 0.036 in 234,090 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (150 hom., cov: 32)
  • Exomes 𝑓: 0.038 (86 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.231

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-15160099-A-G is Benign according to our data. Variant chr19-15160099-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 328363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.*563T>C		3_prime_UTR_variant	Exon 33 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.*563T>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.*563T>C		3_prime_UTR_variant	Exon 33 of 33	1	NM_000435.3	ENSP00000263388.1

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5336 AN: 152142 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.00808

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0377 AC: 3087 AN: 81830 Hom.: 86 Cov.: 0 AF XY: 0.0399 AC XY: 1507 AN XY: 37784

Gnomad4 AFR exome AF: 0.00617

Gnomad4 AMR exome AF: 0.0264

Gnomad4 ASJ exome AF: 0.0825

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0264

Gnomad4 FIN exome AF: 0.0466

Gnomad4 NFE exome AF: 0.0452

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0350 AC: 5335 AN: 152260 Hom.: 150 Cov.: 32 AF XY: 0.0344 AC XY: 2558 AN XY: 74440

Gnomad4 AFR AF: 0.00806

Gnomad4 AMR AF: 0.0301

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.0439

Gnomad4 NFE AF: 0.0523

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0580 Hom.: 48

Bravo AF: 0.0324

Asia WGS AF: 0.00779 AC: 29 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.1
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: rs77669983; hg19: chr19-15270910;