rs1555247853

Variant names:

• chr12-116008553-CCC-TGTTCGAG
• rs1555247853
• NM_015335.5:c.1858_1860delGGGinsCTCGAACA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015335.5(MED13L):​c.1858_1860delGGGinsCTCGAACA​(p.Gly620LeufsTer45) variant causes a frameshift, missense change involving the alteration of a non-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, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.22

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 12-116008553-CCC-TGTTCGAG is Pathogenic according to our data. Variant chr12-116008553-CCC-TGTTCGAG is described in ClinVar as [Pathogenic]. Clinvar id is 521718.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.1858_1860delGGGinsCTCGAACA	p.Gly620LeufsTer45	frameshift_variant, missense_variant	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.1858_1860delGGGinsCTCGAACA	p.Gly620LeufsTer45	frameshift_variant, missense_variant	Exon 10 of 31	1	NM_015335.5	ENSP00000281928.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Apr 19, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected -

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

Mar 02, 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 2018-03-02 and interpreted as Pathogenic. Variant was initially reported on 2017-05-12 by GTR ID of laboratory name 61756. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555247853; hg19: chr12-116446358;