19-15189325-A-G

Position:

chr19-15189325-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000435.3(NOTCH3):c.1140T>C(p.Pro380Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,614,002 control chromosomes in the GnomAD database, including 862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 85 hom., cov: 32)

Exomes 𝑓: 0.029 ( 777 hom. )

Consequence

NOTCH3
NM_000435.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.18

Variant links:

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]

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 19-15189325-A-G is Benign according to our data. Variant chr19-15189325-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15189325-A-G is described in Lovd as [Benign]. Variant chr19-15189325-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.18 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.1140T>C	p.Pro380Pro	synonymous_variant	7/33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 linkuse as main transcript	c.1140T>C	p.Pro380Pro	synonymous_variant	7/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.1140T>C	p.Pro380Pro	synonymous_variant	7/33	1	NM_000435.3	ENSP00000263388.1		Q9UM47
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.1137T>C	p.Pro379Pro	synonymous_variant	7/23	5		ENSP00000473138.1		M0R3C9

Frequencies

GnomAD3 genomes

AF:

0.0267

AC:

4065

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0186

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.0362

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0468

GnomAD3 exomes

AF:

0.0265

AC:

6658

AN:

251294

Hom.:

148

AF XY:

0.0272

AC XY:

3702

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.00751

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0375

GnomAD4 exome

AF:

0.0287

AC:

41895

AN:

1461740

Hom.:

777

Cov.:

AF XY:

0.0288

AC XY:

20950

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.0237

Gnomad4 ASJ exome

AF:

0.114

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0171

Gnomad4 FIN exome

AF:

0.00880

Gnomad4 NFE exome

AF:

0.0296

Gnomad4 OTH exome

AF:

0.0332

GnomAD4 genome

AF:

0.0267

AC:

4064

AN:

152262

Hom.:

Cov.:

AF XY:

0.0260

AC XY:

1933

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0185

Gnomad4 AMR

AF:

0.0362

Gnomad4 ASJ

AF:

0.107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0170

Gnomad4 FIN

AF:

0.00829

Gnomad4 NFE

AF:

0.0298

Gnomad4 OTH

AF:

0.0464

Alfa

AF:

0.0302

Hom.:

Bravo

AF:

0.0283

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0364

EpiControl

AF:

0.0396

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 12, 2021	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 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

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.6

DANN

Benign

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over