19-15167246-A-G

Position:

• chr19-15167246-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.5362+3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 1,610,882 control chromosomes in the GnomAD database, including 643,599 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62203 hom., cov: 33)
  • Exomes 𝑓: 0.89 (581396 hom.)
• Consequence: NOTCH3 NM_000435.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009189
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.160

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-15167246-A-G is Benign according to our data. Variant chr19-15167246-A-G is described in ClinVar as [Benign]. Clinvar id is 256140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15167246-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.5362+3T>C		splice_region_variant, intron_variant		ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.5206+3T>C		splice_region_variant, intron_variant			XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.5362+3T>C		splice_region_variant, intron_variant		1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000595514.1	n.226+3T>C		splice_region_variant, intron_variant		3		ENSP00000470661.1

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137170 AN: 152148 Hom.: 62152 Cov.: 33

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.882

Gnomad NFE AF: 0.899

Gnomad OTH AF: 0.879

GnomAD3 exomes AF: 0.864 AC: 216773 AN: 250944 Hom.: 94311 AF XY: 0.866 AC XY: 117481 AN XY: 135646

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.800

Gnomad SAS exome AF: 0.855

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.862

GnomAD4 exome AF: 0.892 AC: 1300757 AN: 1458616 Hom.: 581396 Cov.: 51 AF XY: 0.890 AC XY: 645481 AN XY: 724940

Gnomad4 AFR exome AF: 0.980

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 0.827

Gnomad4 SAS exome AF: 0.853

Gnomad4 FIN exome AF: 0.887

Gnomad4 NFE exome AF: 0.903

Gnomad4 OTH exome AF: 0.879

GnomAD4 genome AF: 0.902 AC: 137279 AN: 152266 Hom.: 62203 Cov.: 33 AF XY: 0.897 AC XY: 66799 AN XY: 74460

Gnomad4 AFR AF: 0.976

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.851

Gnomad4 FIN AF: 0.883

Gnomad4 NFE AF: 0.899

Gnomad4 OTH AF: 0.880

Alfa AF: 0.909 Hom.: 21385

Bravo AF: 0.896

Asia WGS AF: 0.850 AC: 2955 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
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	-0.46
CADD	Benign	18
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.040		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: rs1548555; hg19: chr19-15278057;