rs61731975

chr19-15160875-G-Achr19-15160875-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000435.3(NOTCH3):c.6753C>T(p.Ser2251=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,613,580 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (150 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (150 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.531

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=-0.54).
• BP6: Variant 19-15160875-G-A is Benign according to our data. Variant chr19-15160875-G-A is described in ClinVar as [Benign]. Clinvar id is 256153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15160875-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.531 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.6753C>T	p.Ser2251=	synonymous_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.6597C>T	p.Ser2199=	synonymous_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.6753C>T	p.Ser2251=	synonymous_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3754 AN: 152146 Hom.: 148 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00641 AC: 1592 AN: 248224 Hom.: 62 AF XY: 0.00458 AC XY: 616 AN XY: 134540

Gnomad AFR exome AF: 0.0895

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00259 AC: 3790 AN: 1461316 Hom.: 150 Cov.: 32 AF XY: 0.00225 AC XY: 1632 AN XY: 726926

Gnomad4 AFR exome AF: 0.0909

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.0248 AC: 3771 AN: 152264 Hom.: 150 Cov.: 32 AF XY: 0.0238 AC XY: 1773 AN XY: 74464

Gnomad4 AFR AF: 0.0867

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0121 Hom.: 30

Bravo AF: 0.0289

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000653

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 18, 2021	- -

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	-0.54
Cadd	Benign	3.5
Dann	Benign	0.70

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: rs61731975; hg19: chr19-15271686;