Variant 8-97644802-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000336273.8(MTDH):c.296C>T(p.Ala99Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MTDH
ENST00000336273.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92

Variant links:

Genes affected

MTDH (HGNC:29608): (metadherin) Enables NF-kappaB binding activity; double-stranded RNA binding activity; and transcription coactivator activity. Involved in several processes, including lipopolysaccharide-mediated signaling pathway; positive regulation of intracellular signal transduction; and regulation of transcription, DNA-templated. Located in endoplasmic reticulum; nuclear lumen; and perinuclear region of cytoplasm. Implicated in hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

MTDH links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1870566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTDH	NM_178812.4 linkuse as main transcript	c.296C>T	p.Ala99Val	missense_variant	1/12	ENST00000336273.8	NP_848927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MTDH	ENST00000336273.8 linkuse as main transcript	c.296C>T	p.Ala99Val	missense_variant	1/12	1	NM_178812.4	ENSP00000338235	P1
MTDH	ENST00000519934.5 linkuse as main transcript	c.227C>T	p.Ala76Val	missense_variant	1/11	5		ENSP00000428168
MTDH	ENST00000522313.1 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/5	4		ENSP00000428703

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000142

AC:

AN:

1405536

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000729

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2021

The c.296C>T (p.A99V) alteration is located in exon 1 (coding exon 1) of the MTDH gene. This alteration results from a C to T substitution at nucleotide position 296, causing the alanine (A) at amino acid position 99 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

0.54

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.032

Sift

Benign

0.056

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.43

B;.

Vest4

0.21

MutPred

0.16

Gain of helix (P = 0.1736);.;

MVP

0.31

MPC

0.42

ClinPred

0.66

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.26

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