rs150222863

chr12-115983328-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015335.5(MED13L):c.4744T>A(p.Ser1582Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,194 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1582F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (24 hom.)
• Consequence: MED13L NM_015335.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.79

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MED13L
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039693713).
• BP6: Variant 12-115983328-A-T is Benign according to our data. Variant chr12-115983328-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 241043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-115983328-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1214/152326) while in subpopulation AFR AF= 0.0272 (1132/41564). AF 95% confidence interval is 0.0259. There are 17 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13L	NM_015335.5	c.4744T>A	p.Ser1582Thr	missense_variant	21/31	ENST00000281928.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13L	ENST00000281928.9	c.4744T>A	p.Ser1582Thr	missense_variant	21/31	1	NM_015335.5	P1

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 1208 AN: 152208 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00221 AC: 554 AN: 251246 Hom.: 8 AF XY: 0.00178 AC XY: 242 AN XY: 135784

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000916 AC: 1339 AN: 1461868 Hom.: 24 Cov.: 32 AF XY: 0.000795 AC XY: 578 AN XY: 727234

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152326 Hom.: 17 Cov.: 32 AF XY: 0.00766 AC XY: 571 AN XY: 74496

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00957

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	- -

MED13L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Transposition of the great arteries, dextro-looped Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.60	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.091
Sift	Benign	0.66	T;.
Sift4G	Benign	0.19	T;.
Polyphen		0.0	B;.
Vest4		0.29
MVP		0.29
MPC		0.55
ClinPred		0.010	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.054
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs150222863; hg19: chr12-116421133; COSMIC: COSV56120365; COSMIC: COSV56120365;