19-15192182-G-T

Position:

• chr19-15192182-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM5 BS2_Supporting

The NM_000435.3(NOTCH3):​c.457C>A​(p.Arg153Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a disulfide_bond (size 9) in uniprot entity NOTC3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000435.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-15192182-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.457C>A	p.Arg153Ser	missense_variant	4/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.457C>A	p.Arg153Ser	missense_variant	4/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.457C>A	p.Arg153Ser	missense_variant	4/33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.454C>A	p.Arg152Ser	missense_variant	4/23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460218 Hom.: 0 Cov.: 40 AF XY: 0.00000413 AC XY: 3 AN XY: 726440

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant, NM_000435.2(NOTCH3):c. 457C>A, has been identified in exon 4 of 33 of the NOTCH3 gene. The variant is predicted to result in a major amino acid change from arginine to serine at position 153 of the protein (NP_000426.2(NOTCH3):p.(Arg153Ser)). The arginine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the EGF-like functional domain. Missense variants result in a loss or a gain of a cysteine residue in one of the 34 EGF-like domains is a known disease mechanism in CADSIL (Joutel, A. et al. (2004)). In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD). An alternative residue change has been reported in the gnomAD database at a frequency of 0.002%. This variant has not been previously reported in clinical cases. A different variant in the same codon resulting in a change to cysteine has been shown to cause CADSIL (ClinVar, Matsushima, T. et al. (2017), Chen, S. et al. (2017)). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.82	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.28
Sift	Benign	0.95	T;.
Sift4G	Benign	0.76	T;T
Polyphen		0.033	B;.
Vest4		0.54
MutPred		0.62		Loss of catalytic residue at R153 (P = 0.0033);.;
MVP		0.92
MPC		0.92
ClinPred		0.65	D
GERP RS		4.9
Varity_R		0.32
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797045014; hg19: chr19-15302993;