rs150811543

Positions:

chr19-15179168-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000435.3(NOTCH3):c.3575C>T(p.Thr1192Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

NOTCH3
NM_000435.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.00700

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:

NOTCH3 (HGNC:):

NOTCH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23131439).

BP6

Variant 19-15179168-G-A is Benign according to our data. Variant chr19-15179168-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447840.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH3	NM_000435.3 linkuse as main transcript	c.3575C>T	p.Thr1192Ile	missense_variant	22/33	ENST00000263388.7	NP_000426.2	Q9UM47
NOTCH3	XM_005259924.5 linkuse as main transcript	c.3419C>T	p.Thr1140Ile	missense_variant	21/32		XP_005259981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NOTCH3	ENST00000263388.7 linkuse as main transcript	c.3575C>T	p.Thr1192Ile	missense_variant	22/33	1	NM_000435.3	ENSP00000263388.1	Q9UM47
NOTCH3	ENST00000601011.1 linkuse as main transcript	c.3416C>T	p.Thr1139Ile	missense_variant	21/23	5		ENSP00000473138.1	M0R3C9
NOTCH3	ENST00000595045.1 linkuse as main transcript	n.411C>T		non_coding_transcript_exon_variant	2/3	2
NOTCH3	ENST00000600841.1 linkuse as main transcript	n.53C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000718

AC:

AN:

250564

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461774

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000893

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.3575C>T (p.T1192I) alteration is located in exon 22 (coding exon 22) of the NOTCH3 gene. This alteration results from a C to T substitution at nucleotide position 3575, causing the threonine (T) at amino acid position 1192 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.14

N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.025

Sift

Benign

0.24

T;.

Sift4G

Benign

0.30

T;T

Polyphen

0.046

B;.

Vest4

0.14

MVP

0.36

MPC

0.92

ClinPred

0.036

GERP RS

0.10

Varity_R

0.074

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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