Variant 8-97687518-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000336273.8(MTDH):c.658A>G(p.Thr220Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MTDH
ENST00000336273.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.86

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTDH	NM_178812.4 linkuse as main transcript	c.658A>G	p.Thr220Ala	missense_variant	4/12	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.658A>G	p.Thr220Ala	missense_variant	4/12	1	NM_178812.4	ENSP00000338235	P1
MTDH	ENST00000519934.5 linkuse as main transcript	c.589A>G	p.Thr197Ala	missense_variant	4/11	5		ENSP00000428168
MTDH	ENST00000522313.1 linkuse as main transcript	c.373A>G	p.Thr125Ala	missense_variant	4/5	4		ENSP00000428703

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250934

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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

Jan 26, 2022

The c.658A>G (p.T220A) alteration is located in exon 4 (coding exon 4) of the MTDH gene. This alteration results from a A to G substitution at nucleotide position 658, causing the threonine (T) at amino acid position 220 to be replaced by an alanine (A). 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

0.058

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.095

N;.

MutationTaster

Benign

0.96

N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.37

N;N

REVEL

Benign

0.042

Sift

Benign

0.56

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0020

B;.

Vest4

0.030

MutPred

0.16

Loss of glycosylation at T220 (P = 0.0363);.;

MVP

0.30

MPC

0.32

ClinPred

0.033

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: 1

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