3-151086942-C-G

Position:

• chr3-151086942-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001393769.1(MED12L):​c.16C>G​(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.60

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.059904456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.16C>G	p.Leu6Val	missense_variant	2/45	ENST00000687756.1	NP_001380698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1	c.16C>G	p.Leu6Val	missense_variant	2/45		NM_001393769.1	ENSP00000508695	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

MED12L-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2024

The MED12L c.16C>G variant is predicted to result in the amino acid substitution p.Leu6Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.0084	.;.;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.060	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	N;N;N;.
MutationTaster	Benign	0.59	N;N;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.070	N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.020	B;B;B;B
Vest4		0.046
MutPred		0.29		Gain of glycosylation at Y9 (P = 0.0017);Gain of glycosylation at Y9 (P = 0.0017);Gain of glycosylation at Y9 (P = 0.0017);Gain of glycosylation at Y9 (P = 0.0017);
MVP		0.068
MPC		1.1
ClinPred		0.54	D
GERP RS		4.6
Varity_R		0.18
gMVP		0.43

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

Other links and lift over

dbSNP: rs532455340; hg19: chr3-150804729;