rs886054260

Variant names:

• chr19-15188301-T-A
• rs886054260
• NM_000435.3:c.1426A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000435.3(NOTCH3):​c.1426A>T​(p.Ser476Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S476N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.66
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-15188301-T-A is Pathogenic according to our data. Variant chr19-15188301-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328411.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.1426A>T	p.Ser476Cys	missense_variant	Exon 9 of 33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.1426A>T	p.Ser476Cys	missense_variant	Exon 9 of 32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.1426A>T	p.Ser476Cys	missense_variant	Exon 9 of 33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.1423A>T	p.Ser475Cys	missense_variant	Exon 9 of 23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455414 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723222

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 43998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 84790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108866

Other (OTH) AF: 0.0000166 AC: 1 AN: 60158

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Nov 15, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.
PhyloP100		4.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.40
MutPred		0.55		Loss of disorder (P = 0.0756);.;
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.81
Mutation Taster		=55/45	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886054260; hg19: chr19-15299112;