rs778882816

Variant names:

• chr3-151086987-C-T
• rs778882816
• NM_001393769.1:c.61C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001393769.1(MED12L):​c.61C>T​(p.Pro21Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.82
• Publications: 1 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: ClinGen, Ambry Genetics, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.61C>T	p.Pro21Ser	missense	Exon 2 of 45	NP_001380698.1	A0A8I5KX78
	MED12L	NM_053002.6		c.61C>T	p.Pro21Ser	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.61C>T	p.Pro21Ser	missense	Exon 2 of 45	ENSP00000508695.1	A0A8I5KX78
	MED12L	ENST00000474524.5	TSL:1	c.61C>T	p.Pro21Ser	missense	Exon 1 of 43	ENSP00000417235.1	Q86YW9-1
	MED12L	ENST00000934759.1		c.61C>T	p.Pro21Ser	missense	Exon 2 of 44	ENSP00000604818.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235660 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458018 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725168

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.0000225 AC: 1 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 85866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110966

Other (OTH) AF: 0.00 AC: 0 AN: 60144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.44		Gain of glycosylation at Y25 (P = 0.0065)
MVP		0.23
MPC		1.2
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		-0.010	Neutral
Varity_R		0.88
gMVP		0.71
Mutation Taster		=47/53	disease causing

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: rs778882816; hg19: chr3-150804774;