19-15160324-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000435.3(NOTCH3):c.*338A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 250,584 control chromosomes in the GnomAD database, including 101,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.90 (61836 hom., cov: 30)
  • Exomes 𝑓: 0.89 (39564 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-15160324-T-G is Benign according to our data. Variant chr19-15160324-T-G is described in ClinVar as [Benign]. Clinvar id is 328368.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.*338A>C		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.*338A>C		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.*338A>C		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.903 AC: 136272 AN: 150960 Hom.: 61794 Cov.: 30

Gnomad AFR AF: 0.977

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.885

Gnomad NFE AF: 0.900

Gnomad OTH AF: 0.878

GnomAD4 exome AF: 0.890 AC: 88619 AN: 99534 Hom.: 39564 Cov.: 0 AF XY: 0.892 AC XY: 41838 AN XY: 46920

Gnomad4 AFR exome AF: 0.982

Gnomad4 AMR exome AF: 0.785

Gnomad4 ASJ exome AF: 0.877

Gnomad4 EAS exome AF: 0.846

Gnomad4 SAS exome AF: 0.898

Gnomad4 FIN exome AF: 0.908

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 0.883

GnomAD4 genome AF: 0.903 AC: 136359 AN: 151050 Hom.: 61836 Cov.: 30 AF XY: 0.899 AC XY: 66318 AN XY: 73806

Gnomad4 AFR AF: 0.977

Gnomad4 AMR AF: 0.784

Gnomad4 ASJ AF: 0.877

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.853

Gnomad4 FIN AF: 0.885

Gnomad4 NFE AF: 0.900

Gnomad4 OTH AF: 0.879

Alfa AF: 0.881 Hom.: 2846

Bravo AF: 0.896

Asia WGS AF: 0.849 AC: 2953 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.80
Dann	Benign	0.42

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: rs7247906; hg19: chr19-15271135;