19-15160566-G-A

Position:

• chr19-15160566-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000435.3(NOTCH3):​c.*96C>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 0.00853 in 1,015,174 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0086 (47 hom.)
• Consequence: NOTCH3 NM_000435.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.178

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=-0.93).
• BP6: Variant 19-15160566-G-A is Benign according to our data. Variant chr19-15160566-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00817 (1244/152260) while in subpopulation AMR AF= 0.0114 (174/15298). AF 95% confidence interval is 0.00999. There are 12 homozygotes in gnomad4. There are 652 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.*96C>T		3_prime_UTR_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.*96C>T		3_prime_UTR_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.*96C>T		3_prime_UTR_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152142 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00859 AC: 7413 AN: 862914 Hom.: 47 Cov.: 12 AF XY: 0.00849 AC XY: 3848 AN XY: 453352

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.00774

Gnomad4 ASJ exome AF: 0.00694

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.00941

Gnomad4 OTH exome AF: 0.00936

GnomAD4 genome AF: 0.00817 AC: 1244 AN: 152260 Hom.: 12 Cov.: 31 AF XY: 0.00876 AC XY: 652 AN XY: 74454

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00899 Hom.: 5

Bravo AF: 0.00704

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.93
CADD	Benign	0.90
DANN	Benign	0.67

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: rs117165744; hg19: chr19-15271377;