chr12-116008723-G-A

Variant names:

• chr12-116008723-G-A
• rs1555247936
• NM_015335.5:c.1690C>T

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.1690C>T​(p.Arg564*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.719
• Publications: 1 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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 12-116008723-G-A is Pathogenic according to our data. Variant chr12-116008723-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 521154.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED13L	NM_015335.5	c.1690C>T	p.Arg564*	stop_gained	Exon 10 of 31	ENST00000281928.9	NP_056150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED13L	ENST00000281928.9	c.1690C>T	p.Arg564*	stop_gained	Exon 10 of 31	1	NM_015335.5	ENSP00000281928.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jun 16, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac anomalies - developmental delay - facial dysmorphism syndrome Pathogenic:1

Oct 15, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-15 and interpreted as Pathogenic. Variant was initially reported on 2016-02-16 by GTR ID of laboratory name 500105. The reporting laboratory might also submit to ClinVar. Inherited from a parent with suspected germline mosaicism and identified in multiple siblings. Additional phenotypic information for other sibling(s) might be available from Simons Searchlight. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		0.72
Vest4		0.36
GERP RS		2.6
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555247936; hg19: chr12-116446528; COSMIC: COSV56115983;