rs114447350

Positions:

• chr19-15161407-G-A
• chr19-15161407-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000435.3(NOTCH3):​c.6221C>T​(p.Pro2074Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00476 in 1,525,304 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (148 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (139 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.61

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=0.001966834).
• BP6: Variant 19-15161407-G-A is Benign according to our data. Variant chr19-15161407-G-A is described in ClinVar as [Benign]. Clinvar id is 256150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15161407-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH3	NM_000435.3	c.6221C>T	p.Pro2074Leu	missense_variant	33/33	ENST00000263388.7
NOTCH3	XM_005259924.5	c.6065C>T	p.Pro2022Leu	missense_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH3	ENST00000263388.7	c.6221C>T	p.Pro2074Leu	missense_variant	33/33	1	NM_000435.3	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3761 AN: 152082 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00563 AC: 702 AN: 124650 Hom.: 30 AF XY: 0.00415 AC XY: 283 AN XY: 68138

Gnomad AFR exome AF: 0.0935

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00254 AC: 3485 AN: 1373104 Hom.: 139 Cov.: 36 AF XY: 0.00221 AC XY: 1491 AN XY: 675262

Gnomad4 AFR exome AF: 0.0918

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.00569

GnomAD4 genome AF: 0.0248 AC: 3778 AN: 152200 Hom.: 148 Cov.: 32 AF XY: 0.0238 AC XY: 1773 AN XY: 74406

Gnomad4 AFR AF: 0.0868

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00745 Hom.: 12

Bravo AF: 0.0289

ESP6500AA AF: 0.0483 AC: 128

ESP6500EA AF: 0.000332 AC: 2

ExAC AF: 0.00251 AC: 240

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

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 18, 2021	- -

Pulmonary arterial hypertension Benign:1

Benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

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 12, 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	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.28	T
Polyphen		0.051	B
Vest4		0.15
MVP		0.90
MPC		0.57
ClinPred		0.0081	T
GERP RS		3.8
Varity_R		0.086
gMVP		0.55

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: rs114447350; hg19: chr19-15272218; COSMIC: COSV54633767; COSMIC: COSV54633767;