rs2074619

chr19-15166108-G-Achr19-15166108-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):c.5363-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.892 in 1,611,540 control chromosomes in the GnomAD database, including 643,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (61879 hom., cov: 32)
  • Exomes 𝑓: 0.89 (581534 hom.)
• Consequence: NOTCH3 NM_000435.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0440

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-15166108-G-A is Benign according to our data. Variant chr19-15166108-G-A is described in ClinVar as [Benign]. Clinvar id is 256141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15166108-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.5363-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263388.7
NOTCH3	XM_005259924.5	c.5207-17C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.5363-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000435.3	P1
NOTCH3	ENST00000595514.1	c.229-593C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.900 AC: 136740 AN: 151956 Hom.: 61832 Cov.: 32

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.876

GnomAD3 exomes AF: 0.862 AC: 214886 AN: 249362 Hom.: 93211 AF XY: 0.864 AC XY: 116581 AN XY: 134916

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.797

Gnomad SAS exome AF: 0.850

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.900

Gnomad OTH exome AF: 0.861

GnomAD4 exome AF: 0.892 AC: 1301240 AN: 1459466 Hom.: 581534 Cov.: 37 AF XY: 0.890 AC XY: 646445 AN XY: 726244

Gnomad4 AFR exome AF: 0.975

Gnomad4 AMR exome AF: 0.721

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 0.826

Gnomad4 SAS exome AF: 0.849

Gnomad4 FIN exome AF: 0.887

Gnomad4 NFE exome AF: 0.903

Gnomad4 OTH exome AF: 0.878

GnomAD4 genome AF: 0.900 AC: 136845 AN: 152074 Hom.: 61879 Cov.: 32 AF XY: 0.895 AC XY: 66550 AN XY: 74326

Gnomad4 AFR AF: 0.971

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.883

Gnomad4 NFE AF: 0.899

Gnomad4 OTH AF: 0.877

Alfa AF: 0.892 Hom.: 11157

Bravo AF: 0.894

Asia WGS AF: 0.843 AC: 2932 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Lateral meningocele syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.90
Dann	Benign	0.23

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: rs2074619; hg19: chr19-15276919;