rs2331652

Variant names:

• chr8-97713742-G-A
• rs2331652
• NM_178812.4:c.1353G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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]

ENSG00000302098 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178812.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTDH	NM_178812.4	MANE Select	c.1353G>A	p.Lys451Lys	synonymous	Exon 9 of 12	NP_848927.2
	MTDH	NM_001363137.1		c.1443G>A	p.Lys481Lys	synonymous	Exon 10 of 13	NP_001350066.1
	MTDH	NM_001363136.1		c.1287G>A	p.Lys429Lys	synonymous	Exon 8 of 11	NP_001350065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTDH	ENST00000336273.8	TSL:1 MANE Select	c.1353G>A	p.Lys451Lys	synonymous	Exon 9 of 12	ENSP00000338235.3
	MTDH	ENST00000519934.5	TSL:5	c.1185G>A	p.Lys395Lys	synonymous	Exon 8 of 11	ENSP00000428168.1
	MTDH	ENST00000521933.1	TSL:5	c.363G>A	p.Lys121Lys	synonymous	Exon 4 of 6	ENSP00000429642.1

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

GnomAD2 exomes AF: 0.0798 AC: 18465 AN: 231460 AF XY: 0.0730

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 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

African (AFR) AF: 0.00520 AC: 172 AN: 33108

American (AMR) AF: 0.242 AC: 10212 AN: 42144

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 396 AN: 25900

East Asian (EAS) AF: 0.203 AC: 7985 AN: 39422

South Asian (SAS) AF: 0.0957 AC: 8066 AN: 84256

European-Finnish (FIN) AF: 0.0441 AC: 2319 AN: 52554

Middle Eastern (MID) AF: 0.0213 AC: 122 AN: 5720

European-Non Finnish (NFE) AF: 0.0155 AC: 17115 AN: 1106246

Other (OTH) AF: 0.0425 AC: 2543 AN: 59844

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

African (AFR) AF: 0.00714 AC: 297 AN: 41588

American (AMR) AF: 0.148 AC: 2256 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3468

East Asian (EAS) AF: 0.241 AC: 1244 AN: 5172

South Asian (SAS) AF: 0.113 AC: 547 AN: 4824

European-Finnish (FIN) AF: 0.0487 AC: 516 AN: 10588

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0159 AC: 1080 AN: 68016

Other (OTH) AF: 0.0464 AC: 98 AN: 2110

Alfa AF: 0.0275 Hom.: 719

Bravo AF: 0.0474

Asia WGS AF: 0.162 AC: 563 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2331652; hg19: chr8-98725970; COSMIC: COSV60343250;