3-151430312-G-C

Position:

• chr3-151430312-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001393769.1(MED12L):​c.6422G>C​(p.Gly2141Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

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]

IGSF10 (HGNC:26384): (immunoglobulin superfamily member 10) Predicted to be involved in regulation of neuron migration. Predicted to act upstream of or within ossification. Located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

MED12L (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• 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=0.26258627).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.6422G>C	p.Gly2141Ala	missense_variant	44/45	ENST00000687756.1	NP_001380698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1	c.6422G>C	p.Gly2141Ala	missense_variant	44/45		NM_001393769.1	ENSP00000508695.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nizon-Isidor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;T
Sift4G	Benign	0.60	T;T
Polyphen		1.0	D;D
Vest4		0.42
MutPred		0.17		Gain of helix (P = 0.0078);.;
MVP		0.068
MPC		1.1
ClinPred		0.85	D
GERP RS		4.2
Varity_R		0.58
gMVP		0.49

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: rs1011092433; hg19: chr3-151148100;