chr19-15197564-C-T

Position:

• chr19-15197564-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000435.3(NOTCH3):​c.133G>A​(p.Asp45Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 30)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67

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 domain EGF-like 1 (size 37) in uniprot entity NOTC3_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_000435.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35426164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3	c.133G>A	p.Asp45Asn	missense_variant	2/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.133G>A	p.Asp45Asn	missense_variant	2/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.133G>A	p.Asp45Asn	missense_variant	2/33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.130G>A	p.Asp44Asn	missense_variant	2/23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151962 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151962 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74218

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0094
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.0	L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.15	T;.
Sift4G	Benign	0.44	T;T
Polyphen		0.067	B;.
Vest4		0.52
MutPred		0.37		Loss of solvent accessibility (P = 0.0595);.;
MVP		1.0
MPC		0.57
ClinPred		0.55	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs142031490; hg19: chr19-15308375; COSMIC: COSV54637111;