rs75617410

chr19-15187325-C-Achr19-15187325-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.1620G>T(p.Thr540=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,490 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T540T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (24 hom.)
• Consequence: NOTCH3 NM_000435.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -6.75

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=-0.69).
• BP6: Variant 19-15187325-C-A is Benign according to our data. Variant chr19-15187325-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 328410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15187325-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00133 (203/152316) while in subpopulation EAS AF= 0.0342 (177/5174). AF 95% confidence interval is 0.0301. There are 3 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.1620G>T	p.Thr540=	synonymous_variant	11/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.1620G>T	p.Thr540=	synonymous_variant	11/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.1620G>T	p.Thr540=	synonymous_variant	11/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.1617G>T	p.Thr539=	synonymous_variant	11/23	5

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152198 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00300 AC: 748 AN: 249694 Hom.: 12 AF XY: 0.00263 AC XY: 355 AN XY: 135218

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.0377

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000973 AC: 1422 AN: 1461174 Hom.: 24 Cov.: 33 AF XY: 0.000927 AC XY: 674 AN XY: 726912

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0299

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00160 AC XY: 119 AN XY: 74474

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.00172

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2020	- -

not specified Benign:1

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	-0.69
Cadd	Benign	0.029
Dann	Benign	0.57

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: rs75617410; hg19: chr19-15298136; COSMIC: COSV99656060;