17-6644582-G-A

Position:

• chr17-6644582-G-A

Variant summary

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

The NM_016060.3(MED31):​c.281C>T​(p.Ala94Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,268 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MED31 NM_016060.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.99

Genes affected

MED31 (HGNC:24260): (mediator complex subunit 31) Predicted to enable transcription coregulator activity and ubiquitin protein ligase activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within limb development and negative regulation of fibroblast proliferation. Predicted to be located in nucleoplasm. Predicted to be part of core mediator complex and mediator complex. [provided by Alliance of Genome Resources, Apr 2022]

TXNDC17 (HGNC:28218): (thioredoxin domain containing 17) Enables peroxidase activity and protein-disulfide reductase (NAD(P)) activity. Involved in tumor necrosis factor-mediated signaling pathway. Located in cytosol. [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=0.30419463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED31	NM_016060.3	c.281C>T	p.Ala94Val	missense_variant	4/4	ENST00000225728.8	NP_057144.1
TXNDC17	NM_032731.4	c.*1563G>A		downstream_gene_variant		ENST00000250101.10	NP_116120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED31	ENST00000225728.8	c.281C>T	p.Ala94Val	missense_variant	4/4	1	NM_016060.3	ENSP00000225728.3
MED31	ENST00000574128.1	c.59C>T	p.Ala20Val	missense_variant	4/4	3		ENSP00000459723.1
MED31	ENST00000575197	c.*52C>T		3_prime_UTR_variant	3/3	2		ENSP00000458248.1
TXNDC17	ENST00000250101.10	c.*1563G>A		downstream_gene_variant		1	NM_032731.4	ENSP00000250101.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461268 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726962

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Nov 17, 2022

The c.281C>T (p.A94V) alteration is located in exon 4 (coding exon 4) of the MED31 gene. This alteration results from a C to T substitution at nucleotide position 281, causing the alanine (A) at amino acid position 94 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	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.75	N;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.23
Sift	Benign	0.20	T;.
Sift4G	Benign	0.91	T;T
Polyphen		0.70	P;.
Vest4		0.50
MutPred		0.49		Gain of ubiquitination at K95 (P = 0.0613);.;
MVP		0.50
MPC		0.74
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.10
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-6547902;