NM_000435.3:c.3399C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000435.3(NOTCH3):c.3399C>A(p.His1133Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,984 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 33)

Exomes 𝑓: 0.017 ( 245 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.668

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:

MIR6795 (HGNC:50031): (microRNA 6795) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6795 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01282531).

BP6

Variant 19-15179425-G-T is Benign according to our data. Variant chr19-15179425-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15179425-G-T is described in Lovd as [Benign]. Variant chr19-15179425-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1793/152156) while in subpopulation NFE AF= 0.0204 (1385/67996). AF 95% confidence interval is 0.0195. There are 18 homozygotes in gnomad4. There are 811 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1793 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH3	NM_000435.3 link	c.3399C>A	p.His1133Gln	missense_variant	Exon 21 of 33	ENST00000263388.7	NP_000426.2	Q9UM47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH3	ENST00000263388.7 link	c.3399C>A	p.His1133Gln	missense_variant	Exon 21 of 33	1	NM_000435.3	ENSP00000263388.1		Q9UM47

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1793

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0204

Gnomad OTH

AF:

0.00671

GnomAD3 exomes

AF:

0.0100

AC:

2514

AN:

251328

Hom.:

AF XY:

0.00980

AC XY:

1332

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0166

AC:

24195

AN:

1461828

Hom.:

245

Cov.:

AF XY:

0.0159

AC XY:

11549

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00309

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000904

Gnomad4 FIN exome

AF:

0.0158

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0118

AC:

1793

AN:

152156

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

811

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0135

Gnomad4 NFE

AF:

0.0204

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0181

AC:

156

ExAC

AF:

0.0102

AC:

1238

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0155

EpiControl

AF:

0.0141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NOTCH3: BS1, BS2 -

Sep 10, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Pulmonary arterial hypertension

Benign:1

Sep 26, 2022

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Uncertain

0.38

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

3.9

DANN

Benign

0.95

DEOGEN2

Uncertain

0.57

D;D

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

N;.

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.29

B;.

Vest4

0.45

MutPred

0.74

Gain of disorder (P = 0.0349);.;

MPC

0.97

ClinPred

0.077

GERP RS

-8.6

Varity_R

0.18

gMVP

0.37

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

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