rs114207045

Positions:

• chr19-15188237-G-A
• chr19-15188237-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP3 BP6_Very_Strong BS1 BS2

The NM_000435.3(NOTCH3):​c.1490C>T​(p.Ser497Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00527 in 1,593,160 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. S497W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0075 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (37 hom.)
• Consequence: NOTCH3 NM_000435.3 missense, splice_region
• Scores: Splicing: ADA: 0.9616
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.28

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 -13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000435.3
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 19-15188237-G-A is Benign according to our data. Variant chr19-15188237-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15188237-G-A is described in Lovd as [Benign]. Variant chr19-15188237-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00746 (1136/152180) while in subpopulation AMR AF= 0.0104 (159/15286). AF 95% confidence interval is 0.00908. There are 6 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	9/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	9/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.1490C>T	p.Ser497Leu	missense_variant, splice_region_variant	9/33	1	NM_000435.3	P1
NOTCH3	ENST00000601011.1	c.1487C>T	p.Ser496Leu	missense_variant, splice_region_variant	9/23	5

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1136 AN: 152062 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00496

Gnomad OTH AF: 0.00959

GnomAD3 exomes AF: 0.00669 AC: 1490 AN: 222722 Hom.: 12 AF XY: 0.00670 AC XY: 805 AN XY: 120082

Gnomad AFR exome AF: 0.00980

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.000466

Gnomad SAS exome AF: 0.00727

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00504 AC: 7256 AN: 1440980 Hom.: 37 Cov.: 31 AF XY: 0.00515 AC XY: 3682 AN XY: 714970

Gnomad4 AFR exome AF: 0.00970

Gnomad4 AMR exome AF: 0.00642

Gnomad4 ASJ exome AF: 0.00682

Gnomad4 EAS exome AF: 0.000306

Gnomad4 SAS exome AF: 0.00625

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00724

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152180 Hom.: 6 Cov.: 32 AF XY: 0.00785 AC XY: 584 AN XY: 74398

Gnomad4 AFR AF: 0.00968

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.00496

Gnomad4 OTH AF: 0.00949

Alfa AF: 0.00530 Hom.: 0

Bravo AF: 0.00691

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00569 AC: 687

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NOTCH3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Lateral meningocele syndrome;C3809084:Myofibromatosis, infantile, 2;C4551768:Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0081
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.26
Sift	Benign	0.47	T;.
Sift4G	Benign	0.50	T;D
Polyphen		0.065	B;.
Vest4		0.31
MVP		0.99
MPC		0.42
ClinPred		0.021	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.76
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: rs114207045; hg19: chr19-15299048; COSMIC: COSV54626981;