X-71128466-A-G

Variant names:

• chrX-71128466-A-G
• rs749625903
• NM_005120.3:c.3354+26A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005120.3(MED12):​c.3354+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,208,064 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000030 (0 hom. 12 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00500
• 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: Labcorp Genetics (formerly Invitae), G2P, 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-71128466-A-G is Benign according to our data. Variant chrX-71128466-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 259635.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.3354+26A>G		intron_variant	Intron 23 of 44	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.3354+26A>G		intron_variant	Intron 23 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.00000906 AC: 1 AN: 110423 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000772 AC: 14 AN: 181438 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000614

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 33 AN: 1097641 Hom.: 0 Cov.: 32 AF XY: 0.0000331 AC XY: 12 AN XY: 363079

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.000980 AC: 19 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3995

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 841974

Other (OTH) AF: 0.00 AC: 0 AN: 46066

GnomAD4 genome AF: 0.00000906 AC: 1 AN: 110423 Hom.: 0 Cov.: 22 AF XY: 0.0000306 AC XY: 1 AN XY: 32651

African (AFR) AF: 0.00 AC: 0 AN: 30189

American (AMR) AF: 0.00 AC: 0 AN: 10442

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52801

Other (OTH) AF: 0.00 AC: 0 AN: 1487

Alfa AF: 0.000144 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.66
PhyloP100		-0.0050
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: rs749625903; hg19: chrX-70348316;