19-15180732-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000435.3(NOTCH3):c.3091C>G(p.Arg1031Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,552 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign 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. R1031C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain EGF-like 26 (size 34) in uniprot entity NOTC3_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) 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 chr19-15180732-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.3091C>G	p.Arg1031Gly	missense_variant	19/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.2935C>G	p.Arg979Gly	missense_variant	18/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.3091C>G	p.Arg1031Gly	missense_variant	19/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.2932C>G	p.Arg978Gly	missense_variant	18/23	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423552 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 704652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000262

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.86	D;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.45
Sift	Benign	0.37	T;.
Sift4G	Benign	0.39	T;T
Polyphen		0.091	B;.
Vest4		0.46
MutPred		0.71		Loss of stability (P = 0.0434);.;
MVP		0.97
MPC		0.82
ClinPred		0.22	T
GERP RS		3.1
Varity_R		0.27
gMVP		0.81

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: rs1285584068; hg19: chr19-15291543;