chr3-151086976-C-T

Variant names:

• chr3-151086976-C-T
• rs1354698930
• NM_001393769.1:c.50C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001393769.1(MED12L):​c.50C>T​(p.Pro17Leu) variant causes a missense change. 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: 6.83
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Nizon-Isidor syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26920894).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393769.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	NM_001393769.1	MANE Select	c.50C>T	p.Pro17Leu	missense	Exon 2 of 45	NP_001380698.1	A0A8I5KX78
	MED12L	NM_053002.6		c.50C>T	p.Pro17Leu	missense	Exon 2 of 44	NP_443728.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	ENST00000687756.1	MANE Select	c.50C>T	p.Pro17Leu	missense	Exon 2 of 45	ENSP00000508695.1	A0A8I5KX78
	MED12L	ENST00000474524.5	TSL:1	c.50C>T	p.Pro17Leu	missense	Exon 1 of 43	ENSP00000417235.1	Q86YW9-1
	MED12L	ENST00000934759.1		c.50C>T	p.Pro17Leu	missense	Exon 2 of 44	ENSP00000604818.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.22
Sift	Benign	0.18	T
Sift4G	Uncertain	0.045	D
Polyphen		0.83	P
Vest4		0.47
MutPred		0.30		Loss of glycosylation at K15 (P = 0.0419)
MVP		0.11
MPC		0.49
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		0.089	Neutral
Varity_R		0.44
gMVP		0.55
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs1354698930; hg19: chr3-150804763;