rs1555730204

Positions:

• chr19-15197569-C-A
• chr19-15197569-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000263388.7(NOTCH3):​c.128G>T​(p.Cys43Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C43Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NOTCH3 ENST00000263388.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 12) in uniprot entity NOTC3_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000263388.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-15197568-GC-AT is described in ClinVar as [Pathogenic]. Clinvar id is 1807364.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.128G>T	p.Cys43Phe	missense_variant	2/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.128G>T	p.Cys43Phe	missense_variant	2/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.128G>T	p.Cys43Phe	missense_variant	2/33	1	NM_000435.3	ENSP00000263388	P1
NOTCH3	ENST00000601011.1	c.125G>T	p.Cys42Phe	missense_variant	2/23	5		ENSP00000473138

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;T
Eigen	Benign	0.014
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.90	P;.
Vest4		0.74
MutPred		0.99		Loss of glycosylation at S47 (P = 0.0692);.;
MVP		1.0
MPC		1.6
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.97
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15308380;