19-15160118-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000435.3(NOTCH3):c.*544C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 234,816 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (4 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.283

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=-0.62).
• BP6: Variant 19-15160118-G-A is Benign according to our data. Variant chr19-15160118-G-A is described in ClinVar as [Benign]. Clinvar id is 328364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00408 (621/152290) while in subpopulation SAS AF= 0.0089 (43/4830). AF 95% confidence interval is 0.00679. There are 7 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 622 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.*544C>T		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.*544C>T		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.*544C>T		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152172 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00554 AC: 457 AN: 82526 Hom.: 4 Cov.: 0 AF XY: 0.00547 AC XY: 209 AN XY: 38196

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.000175

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00561

Gnomad4 OTH exome AF: 0.00587

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152290 Hom.: 7 Cov.: 33 AF XY: 0.00379 AC XY: 282 AN XY: 74466

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00398

Asia WGS AF: 0.00375 AC: 13 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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.7
Dann	Benign	0.85

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: rs368577217; hg19: chr19-15270929;