3-151087022-G-C

Position:

• chr3-151087022-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001393769.1(MED12L):​c.96G>C​(p.Lys32Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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 2 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=0.31439632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.96G>C	p.Lys32Asn	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.96G>C	p.Lys32Asn	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: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	L;L;L;.
MutationTaster	Benign	0.98	D;D;D;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.40
MutPred		0.29		Loss of ubiquitination at K32 (P = 0.0039);Loss of ubiquitination at K32 (P = 0.0039);Loss of ubiquitination at K32 (P = 0.0039);Loss of ubiquitination at K32 (P = 0.0039);
MVP		0.18
MPC		0.47
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.54
gMVP		0.67

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: chr3-150804809;