3-151122797-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001393769.1(MED12L):c.219T>G(p.Phe73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.260

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MED12L

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12L	NM_001393769.1	c.219T>G	p.Phe73Leu	missense_variant	4/45	ENST00000687756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12L	ENST00000687756.1	c.219T>G	p.Phe73Leu	missense_variant	4/45		NM_001393769.1	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.219T>G (p.F73L) alteration is located in exon 3 (coding exon 3) of the MED12L gene. This alteration results from a T to G substitution at nucleotide position 219, causing the phenylalanine (F) at amino acid position 73 to be replaced by a leucine (L). 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	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	0.017
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.7	L;L;L;.
MutationTaster	Benign	0.98	D;D;D;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.042	D;D;T;T
Polyphen		0.99	D;D;P;D
Vest4		0.84
MutPred		0.47		Gain of ubiquitination at K68 (P = 0.0846);Gain of ubiquitination at K68 (P = 0.0846);Gain of ubiquitination at K68 (P = 0.0846);Gain of ubiquitination at K68 (P = 0.0846);
MVP		0.30
MPC		1.3
ClinPred		1.0	D
GERP RS		-1.4
Varity_R		0.54
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-150840584;