19-15192182-G-T

Variant names:

• chr19-15192182-G-T
• rs797045014
• NM_000435.3:c.457C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM5

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. R153H) has been classified as Likely 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
• Publications: 51 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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000435.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-15192182-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.457C>A	p.Arg153Ser	missense_variant	Exon 4 of 33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.454C>A	p.Arg152Ser	missense_variant	Exon 4 of 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		4.8
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
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs797045014; hg19: chr19-15302993;