rs1044008

chr19-15161190-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000435.3(NOTCH3):c.6438G>A(p.Ala2146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,539,680 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (111 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1220 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.73

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-15161190-C-T is Benign according to our data. Variant chr19-15161190-C-T is described in ClinVar as [Benign]. Clinvar id is 256151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15161190-C-T is described in Lovd as [Benign]. Variant chr19-15161190-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0311 (4732/152282) while in subpopulation NFE AF= 0.043 (2926/67996). AF 95% confidence interval is 0.0417. There are 111 homozygotes in gnomad4. There are 2366 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 4733 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.6438G>A	p.Ala2146=	synonymous_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.6282G>A	p.Ala2094=	synonymous_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.6438G>A	p.Ala2146=	synonymous_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4733 AN: 152164 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.0543

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0430

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0319 AC: 4332 AN: 135802 Hom.: 80 AF XY: 0.0308 AC XY: 2285 AN XY: 74102

Gnomad AFR exome AF: 0.00608

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00178

Gnomad SAS exome AF: 0.0127

Gnomad FIN exome AF: 0.0549

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0397 AC: 55073 AN: 1387398 Hom.: 1220 Cov.: 37 AF XY: 0.0391 AC XY: 26792 AN XY: 684784

Gnomad4 AFR exome AF: 0.00641

Gnomad4 AMR exome AF: 0.0408

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.000686

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.0570

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0361

GnomAD4 genome AF: 0.0311 AC: 4732 AN: 152282 Hom.: 111 Cov.: 32 AF XY: 0.0318 AC XY: 2366 AN XY: 74452

Gnomad4 AFR AF: 0.00775

Gnomad4 AMR AF: 0.0368

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0543

Gnomad4 NFE AF: 0.0430

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0388 Hom.: 28

Bravo AF: 0.0302

Asia WGS AF: 0.00982 AC: 35 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.14
Dann	Benign	0.25

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: rs1044008; hg19: chr19-15272001;