rs778103349

Variant names:

• chrX-71141283-G-A
• rs778103349
• NM_005120.3:c.6321G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_005120.3(MED12):​c.6321G>A​(p.Gln2107Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000956 in 1,045,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0910
• Publications: 0 publications found

Genes affected

MED12 (HGNC:11957): (mediator complex subunit 12) The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome. [provided by RefSeq, Aug 2009]

MED12 Gene-Disease associations (from GenCC):

• FG syndrome 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• MED12-related intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant X-71141283-G-A is Benign according to our data. Variant chrX-71141283-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 458831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.091 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. 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
	MED12	NM_005120.3	MANE Select	c.6321G>A	p.Gln2107Gln	synonymous	Exon 43 of 45	NP_005111.2	Q93074-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.6321G>A	p.Gln2107Gln	synonymous	Exon 43 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.6330G>A	p.Gln2110Gln	synonymous	Exon 43 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.6363G>A	p.Gln2121Gln	synonymous	Exon 43 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.56e-7 AC: 1 AN: 1045504 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 340264

⚠️ 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: 24806

American (AMR) AF: 0.0000359 AC: 1 AN: 27890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18458

East Asian (EAS) AF: 0.00 AC: 0 AN: 27125

South Asian (SAS) AF: 0.00 AC: 0 AN: 49780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37507

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4017

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811871

Other (OTH) AF: 0.00 AC: 0 AN: 44050

⚠️ 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.: 23

Alfa AF: 0.000169 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.18
DANN	Benign	0.73
PhyloP100		-0.091
Mutation Taster		=100/0	polymorphism

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: rs778103349; hg19: chrX-70361133;