rs869025287

Variant names:

• chr12-115969039-TAATATGCC-T
• rs869025287
• NM_015335.5:c.6118_6125delGGCATATT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015335.5(MED13L):​c.6118_6125delGGCATATT​(p.Gly2040AsnfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED13L NM_015335.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.10
• Publications: 2 publications found

Genes affected

MED13L (HGNC:22962): (mediator complex subunit 13L) The protein encoded by this gene is a subunit of the Mediator complex, a large complex of proteins that functions as a transcriptional coactivator for most RNA polymerase II-transcribed genes. The encoded protein is involved in early development of the heart and brain. Defects in this gene are a cause of transposition of the great arteries, dextro-looped (DTGA).[provided by RefSeq, Jul 2010]

MED13L Gene-Disease associations (from GenCC):

• cardiac anomalies - developmental delay - facial dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-115969039-TAATATGCC-T is Pathogenic according to our data. Variant chr12-115969039-TAATATGCC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 221556.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015335.5. 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
	MED13L	NM_015335.5	MANE Select	c.6118_6125delGGCATATT	p.Gly2040AsnfsTer32	frameshift	Exon 28 of 31	NP_056150.1	Q71F56

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED13L	ENST00000281928.9	TSL:1 MANE Select	c.6118_6125delGGCATATT	p.Gly2040AsnfsTer32	frameshift	Exon 28 of 31	ENSP00000281928.3	Q71F56
	MED13L	ENST00000650226.1		c.6154_6161delGGCATATT	p.Gly2052AsnfsTer32	frameshift	Exon 28 of 31	ENSP00000496981.1	A0A3B3IRX3
	MED13L	ENST00000649607.1		c.4300_4307delGGCATATT	p.Gly1434fs	frameshift	Exon 19 of 22	ENSP00000497064.1	A0A3B3IS46

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiac anomalies - developmental delay - facial dysmorphism syndrome (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025287; hg19: chr12-116406844;