8-97644813-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_178812.4(MTDH):c.307C>G(p.Leu103Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,574,454 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (28 hom.)
• Consequence: MTDH NM_178812.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.205

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023199022).
• BP6: Variant 8-97644813-C-G is Benign according to our data. Variant chr8-97644813-C-G is described in ClinVar as [Benign]. Clinvar id is 2658702.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00319 (4541/1422098) while in subpopulation MID AF= 0.0247 (138/5588). AF 95% confidence interval is 0.0213. There are 28 homozygotes in gnomad4_exome. There are 2442 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTDH	NM_178812.4	c.307C>G	p.Leu103Val	missense_variant	1/12	ENST00000336273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTDH	ENST00000336273.8	c.307C>G	p.Leu103Val	missense_variant	1/12	1	NM_178812.4	P1
MTDH	ENST00000519934.5	c.238C>G	p.Leu80Val	missense_variant	1/11	5
MTDH	ENST00000522313.1	c.22C>G	p.Leu8Val	missense_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.00755 AC: 1149 AN: 152240 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00951

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00489 AC: 965 AN: 197530 Hom.: 8 AF XY: 0.00503 AC XY: 560 AN XY: 111256

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.00608

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00879

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00737

GnomAD4 exome AF: 0.00319 AC: 4541 AN: 1422098 Hom.: 28 Cov.: 31 AF XY: 0.00345 AC XY: 2442 AN XY: 707856

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.00657

Gnomad4 ASJ exome AF: 0.0329

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.00946

Gnomad4 FIN exome AF: 0.000117

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.00756 AC: 1152 AN: 152356 Hom.: 10 Cov.: 32 AF XY: 0.00769 AC XY: 573 AN XY: 74510

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00952

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00565 Hom.: 1

Bravo AF: 0.00853

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00943 AC: 35

ESP6500EA AF: 0.00185 AC: 14

ExAC AF: 0.00490 AC: 580

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

MTDH: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	12
Dann	Benign	0.81
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.047
Sift	Benign	0.68	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0	B;.
Vest4		0.091
MVP		0.10
MPC		0.32
ClinPred		0.00096	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.30

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

Other links and lift over

dbSNP: rs188271601; hg19: chr8-98657041; COSMIC: COSV99079992;