chr19-15159994-C-A

Variant names:

• chr19-15159994-C-A
• rs1044055
• NM_000435.3:c.*668G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.336

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 -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 rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.*668G>T		3_prime_UTR_variant	Exon 33 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.*668G>T		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.*668G>T		3_prime_UTR_variant	Exon 33 of 33	1	NM_000435.3	ENSP00000263388.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103901 AN: 152030 Hom.: 36406 Cov.: 33

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.: 0 AF XY: 0.723 AC XY: 27008 AN XY: 37348

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.: 33 AF XY: 0.683 AC XY: 50810 AN XY: 74378

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

Submissions by phenotype

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.68
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

Other links and lift over

dbSNP: rs1044055; hg19: chr19-15270805; COSMIC: COSV54630515; COSMIC: COSV54630515;