19-15185592-C-G

Position:

• chr19-15185592-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000435.3(NOTCH3):​c.2039G>C​(p.Arg680Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,312 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R680H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00

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 Likely_benign. Variant got -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 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.2039G>C	p.Arg680Pro	missense_variant	13/33	ENST00000263388.7	NP_000426.2
NOTCH3	XM_005259924.5	c.2039G>C	p.Arg680Pro	missense_variant	13/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7	c.2039G>C	p.Arg680Pro	missense_variant	13/33	1	NM_000435.3	ENSP00000263388.1
NOTCH3	ENST00000601011.1	c.2036G>C	p.Arg679Pro	missense_variant	13/23	5		ENSP00000473138.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461312 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

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

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.024	D;.
Sift4G	Benign	0.17	T;T
Polyphen		0.75	P;.
Vest4		0.66
MutPred		0.48		Gain of catalytic residue at R680 (P = 0.0943);.;
MVP		0.99
MPC		0.89
ClinPred		0.77	D
GERP RS		-3.5
Varity_R		0.48
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs10406745; hg19: chr19-15296403;