rs1555729486

Positions:

• chr19-15192118-C-A
• chr19-15192118-C-G
• chr19-15192118-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000435.3(NOTCH3):​c.521G>T​(p.Cys174Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C174Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.74

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 14 ACMG points.

• PS1: Transcript NM_000435.3 (NOTCH3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a domain EGF-like 4; calcium-binding (size 37) in uniprot entity NOTC3_HUMAN there are 37 pathogenic changes around while only 1 benign (97%) in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-15192118-C-A is Pathogenic according to our data. Variant chr19-15192118-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 447855.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-15192118-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.521G>T	p.Cys174Phe	missense_variant	4/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.521G>T	p.Cys174Phe	missense_variant	4/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.521G>T	p.Cys174Phe	missense_variant	4/33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.518G>T	p.Cys173Phe	missense_variant	4/23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 04, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	5.0	H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.5	D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		1.0		Loss of glycosylation at T173 (P = 0.1329);.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.98

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: rs1555729486; hg19: chr19-15302929;