rs2331652

Positions:

• chr8-97713742-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_178812.4(MTDH):​c.1353G>A​(p.Lys451Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0344 in 1,601,432 control chromosomes in the GnomAD database, including 3,562 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (459 hom., cov: 33)
  • Exomes 𝑓: 0.034 (3103 hom.)
• Consequence: MTDH NM_178812.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.42

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTDH	NM_178812.4	c.1353G>A	p.Lys451Lys	synonymous_variant	9/12	ENST00000336273.8	NP_848927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTDH	ENST00000336273.8	c.1353G>A	p.Lys451Lys	synonymous_variant	9/12	1	NM_178812.4	ENSP00000338235.3

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6076 AN: 152116 Hom.: 454 Cov.: 33

Gnomad AFR AF: 0.00716

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0798 AC: 18465 AN: 231460 Hom.: 1919 AF XY: 0.0730 AC XY: 9169 AN XY: 125642

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.245

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0549

GnomAD4 exome AF: 0.0338 AC: 48930 AN: 1449194 Hom.: 3103 Cov.: 29 AF XY: 0.0345 AC XY: 24821 AN XY: 720470

Gnomad4 AFR exome AF: 0.00520

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0425

GnomAD4 genome AF: 0.0400 AC: 6089 AN: 152238 Hom.: 459 Cov.: 33 AF XY: 0.0455 AC XY: 3387 AN XY: 74448

Gnomad4 AFR AF: 0.00714

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0487

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0464

Alfa AF: 0.0252 Hom.: 413

Bravo AF: 0.0474

Asia WGS AF: 0.162 AC: 563 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2331652; hg19: chr8-98725970; COSMIC: COSV60343250;