19-15201219-C-A

Variant names:

• chr19-15201219-C-A
• rs11882186
• NM_000435.3:c.-314G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000435.3(NOTCH3):​c.-314G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 151,520 control chromosomes in the GnomAD database, including 3,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3628 hom., cov: 30)
• Consequence: NOTCH3 NM_000435.3 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.186
• Publications: 3 publications found

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]

NOTCH3 Gene-Disease associations (from GenCC):

• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myofibromatosis, infantile, 2

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-15201219-C-A is Benign according to our data. Variant chr19-15201219-C-A is described in ClinVar as Benign. ClinVar VariationId is 1180159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.-314G>T		upstream_gene_variant		ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.-314G>T		upstream_gene_variant			XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.-314G>T		upstream_gene_variant		1	NM_000435.3	ENSP00000263388.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29229 AN: 151412 Hom.: 3614 Cov.: 30

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0786

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.193 AC: 29271 AN: 151520 Hom.: 3628 Cov.: 30 AF XY: 0.191 AC XY: 14129 AN XY: 74006

African (AFR) AF: 0.339 AC: 14026 AN: 41366

American (AMR) AF: 0.167 AC: 2535 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 552 AN: 3458

East Asian (EAS) AF: 0.348 AC: 1773 AN: 5090

South Asian (SAS) AF: 0.140 AC: 674 AN: 4798

European-Finnish (FIN) AF: 0.0786 AC: 830 AN: 10564

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8381 AN: 67760

Other (OTH) AF: 0.172 AC: 361 AN: 2094

Alfa AF: 0.142 Hom.: 763

Bravo AF: 0.211

Asia WGS AF: 0.241 AC: 835 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.62
PhyloP100		0.19
PromoterAI		0.14	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11882186; hg19: chr19-15312030;