rs140040122

chr19-15185351-G-Achr19-15185351-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000435.3(NOTCH3):c.2202C>T(p.Ala734=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,612,552 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (8 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.361

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-15185351-G-A is Benign according to our data. Variant chr19-15185351-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15185351-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.361 with no splicing effect.
• BS2: High AC in GnomAd at 376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.2202C>T	p.Ala734=	synonymous_variant	14/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.2202C>T	p.Ala734=	synonymous_variant	14/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.2202C>T	p.Ala734=	synonymous_variant	14/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.2199C>T	p.Ala733=	synonymous_variant	14/23	5

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 376 AN: 151894 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000823

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00210 AC: 516 AN: 245730 Hom.: 0 AF XY: 0.00225 AC XY: 302 AN XY: 134046

Gnomad AFR exome AF: 0.000850

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00315 AC: 4597 AN: 1460540 Hom.: 8 Cov.: 33 AF XY: 0.00304 AC XY: 2206 AN XY: 726590

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00206

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00247 AC: 375 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.00221 AC XY: 164 AN XY: 74308

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00389

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00234

EpiCase AF: 0.00305

EpiControl AF: 0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NOTCH3: BP4, BP7, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:1

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. -

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.7
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140040122; hg19: chr19-15296162; COSMIC: COSV54626073;