Genetic Variant MED31:p.Gly41Asp (chr17-6650063-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016060.3(MED31):c.122G>A(p.Gly41Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MED31
NM_016060.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.65

Publications

0 publications found

Variant links:

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]

MED31 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

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.122G>A	p.Gly41Asp	missense	Exon 3 of 4	NP_057144.1	Q9Y3C7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MED31	ENST00000225728.8	TSL:1 MANE Select	c.122G>A	p.Gly41Asp	missense	Exon 3 of 4	ENSP00000225728.3	Q9Y3C7
MED31	ENST00000574128.1	TSL:3	c.-101G>A		5_prime_UTR	Exon 3 of 4	ENSP00000459723.1	I3L2J1
MED31	ENST00000575197.1	TSL:2	c.106+293G>A		intron	N/A	ENSP00000458248.1	I3L0P8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717522

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31984

American (AMR)

AF:

0.00

AC:

AN:

39544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25388

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.00

AC:

AN:

81226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107376

Other (OTH)

AF:

0.00

AC:

AN:

59578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.0060

MutationAssessor

Uncertain

2.9

PhyloP100

5.6

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.7

REVEL

Uncertain

0.40

Sift

Benign

0.042

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.81

MutPred

0.60

Gain of solvent accessibility (P = 0.0648)

MVP

0.80

MPC

1.8

ClinPred

0.99

GERP RS

5.6

Varity_R

0.77

gMVP

0.72

Mutation Taster

=192/108

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over