rs78926093

chr19-15177884-G-Achr19-15177884-G-Cchr19-15177884-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000435.3(NOTCH3):c.4044C>T(p.Gly1348=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,240,736 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.199

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=-0.6).
• BP6: Variant 19-15177884-G-A is Benign according to our data. Variant chr19-15177884-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256135.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=1}. Variant chr19-15177884-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.199 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00742 (1124/151438) while in subpopulation AFR AF= 0.0193 (799/41462). AF 95% confidence interval is 0.0182. There are 6 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.4044C>T	p.Gly1348=	synonymous_variant	24/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.3888C>T	p.Gly1296=	synonymous_variant	23/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.4044C>T	p.Gly1348=	synonymous_variant	24/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1119 AN: 151328 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00606

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000977

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00818

GnomAD4 exome AF: 0.00228 AC: 2482 AN: 1089298 Hom.: 11 Cov.: 32 AF XY: 0.00226 AC XY: 1167 AN XY: 516988

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000443

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.00742 AC: 1124 AN: 151438 Hom.: 6 Cov.: 31 AF XY: 0.00713 AC XY: 528 AN XY: 74004

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.00605

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000977

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00809

Alfa AF: 0.00728 Hom.: 0

Bravo AF: 0.00839

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2017	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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	-0.60
Cadd	Benign	12
Dann	Benign	0.96

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: rs78926093; hg19: chr19-15288695;