Variant 3-151122971-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001393769.1(MED12L):c.393A>T(p.Lys131Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MED12L
NM_001393769.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50

Variant links:

Genes affected

MED12L (HGNC:16050): (mediator complex subunit 12L) The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

MED12L links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED12L. . Gene score misZ 3.132 (greater than the threshold 3.09). Trascript score misZ 3.991 (greater than threshold 3.09). GenCC has associacion of gene with Nizon-Isidor syndrome, autosomal dominant non-syndromic intellectual disability.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12L	NM_001393769.1 linkuse as main transcript	c.393A>T	p.Lys131Asn	missense_variant	4/45	ENST00000687756.1	NP_001380698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1 linkuse as main transcript	c.393A>T	p.Lys131Asn	missense_variant	4/45		NM_001393769.1	ENSP00000508695	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1449018

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.393A>T (p.K131N) alteration is located in exon 3 (coding exon 3) of the MED12L gene. This alteration results from a A to T substitution at nucleotide position 393, causing the lysine (K) at amino acid position 131 to be replaced by an asparagine (N). 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

0.99

BayesDel_addAF

Benign

0.0067

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Uncertain

0.013

MutationAssessor

Uncertain

2.3

M;M;M;.

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.71

MutPred

0.54

Loss of methylation at K131 (P = 0.0259);Loss of methylation at K131 (P = 0.0259);Loss of methylation at K131 (P = 0.0259);Loss of methylation at K131 (P = 0.0259);

MVP

0.17

MPC

1.3

ClinPred

0.99

GERP RS

5.4

Varity_R

0.77

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over