8-97689052-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178812.4(MTDH):c.760A>G(p.Asn254Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000913 in 1,423,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: MTDH NM_178812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3039063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTDH	NM_178812.4	c.760A>G	p.Asn254Asp	missense_variant	5/12	ENST00000336273.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTDH	ENST00000336273.8	c.760A>G	p.Asn254Asp	missense_variant	5/12	1	NM_178812.4	P1
MTDH	ENST00000519934.5	c.691A>G	p.Asn231Asp	missense_variant	5/11	5
MTDH	ENST00000522313.1	c.459+1447A>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000913 AC: 13 AN: 1423186 Hom.: 0 Cov.: 25 AF XY: 0.00000705 AC XY: 5 AN XY: 708986

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: 0.0000120

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

Dec 06, 2023

The c.760A>G (p.N254D) alteration is located in exon 5 (coding exon 5) of the MTDH gene. This alteration results from a A to G substitution at nucleotide position 760, causing the asparagine (N) at amino acid position 254 to be replaced by an aspartic acid (D). 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	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.089	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.16
Sift	Benign	0.18	T;T
Sift4G	Benign	0.33	T;T
Polyphen		1.0	D;.
Vest4		0.36
MutPred		0.32		Loss of sheet (P = 0.0315);.;
MVP		0.63
MPC		1.1
ClinPred		0.88	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr8-98701280;