NM_016060.3:c.281C>T

Variant names:

• chr17-6644582-G-A
• NM_016060.3:c.281C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A94S) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30419463).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016060.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED31	NM_016060.3	MANE Select	c.281C>T	p.Ala94Val	missense	Exon 4 of 4	NP_057144.1	Q9Y3C7
	TXNDC17	NM_032731.4	MANE Select	c.*1563G>A		downstream_gene	N/A	NP_116120.1	A0A140VJY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED31	ENST00000225728.8	TSL:1 MANE Select	c.281C>T	p.Ala94Val	missense	Exon 4 of 4	ENSP00000225728.3	Q9Y3C7
	MED31	ENST00000574128.1	TSL:3	c.59C>T	p.Ala20Val	missense	Exon 4 of 4	ENSP00000459723.1	I3L2J1
	MED31	ENST00000575197.1	TSL:2	c.*52C>T		3_prime_UTR	Exon 3 of 3	ENSP00000458248.1	I3L0P8

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

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111904

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.75	N
PhyloP100		9.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.23
Sift	Benign	0.20	T
Sift4G	Benign	0.91	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
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

hg19: chr17-6547902;