rs78501403

chr19-15174125-C-Gchr19-15174125-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000435.3(NOTCH3):c.4679G>C(p.Arg1560Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000893 in 1,604,112 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1560Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.90

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009254307).
• BP6: Variant 19-15174125-C-G is Benign according to our data. Variant chr19-15174125-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15174125-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00462 (704/152368) while in subpopulation AFR AF= 0.016 (666/41586). AF 95% confidence interval is 0.015. There are 7 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 699 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.4679G>C	p.Arg1560Pro	missense_variant	25/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.4523G>C	p.Arg1508Pro	missense_variant	24/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.4679G>C	p.Arg1560Pro	missense_variant	25/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.00459 AC: 699 AN: 152250 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00115 AC: 279 AN: 242438 Hom.: 0 AF XY: 0.000853 AC XY: 113 AN XY: 132542

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000728

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000923

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000501 AC: 728 AN: 1451744 Hom.: 2 Cov.: 30 AF XY: 0.000429 AC XY: 309 AN XY: 720518

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.000832

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000181

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152368 Hom.: 7 Cov.: 32 AF XY: 0.00437 AC XY: 326 AN XY: 74518

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000273 Hom.: 0

Bravo AF: 0.00535

ESP6500AA AF: 0.0103 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	This variant is associated with the following publications: (PMID: 24086431) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 19, 2021	- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.61
Sift	Benign	0.24	T
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.67
MVP		1.0
MPC		1.8
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.89
gMVP		0.99

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: rs78501403; hg19: chr19-15284936; COSMIC: COSV54635596; COSMIC: COSV54635596;