8-97661097-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178812.4(MTDH):c.407C>T(p.Ala136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A136T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MTDH NM_178812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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]

ACMG classification

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=0.108246386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTDH	NM_178812.4	c.407C>T	p.Ala136Val	missense_variant	2/12	ENST00000336273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTDH	ENST00000336273.8	c.407C>T	p.Ala136Val	missense_variant	2/12	1	NM_178812.4	P1
MTDH	ENST00000519934.5	c.338C>T	p.Ala113Val	missense_variant	2/11	5
MTDH	ENST00000522313.1	c.122C>T	p.Ala41Val	missense_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460914 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726698

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.407C>T (p.A136V) alteration is located in exon 2 (coding exon 2) of the MTDH gene. This alteration results from a C to T substitution at nucleotide position 407, causing the alanine (A) at amino acid position 136 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	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Uncertain	24
Dann	Benign	0.91
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.066
Sift	Benign	0.58	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.069	B;.
Vest4		0.34
MutPred		0.16		Gain of sheet (P = 0.0344);.;
MVP		0.21
MPC		0.32
ClinPred		0.20	T
GERP RS		3.7
Varity_R		0.056
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-98673325;