rs150222863

Positions:

chr12-115983328-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0080 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 24 hom. )

Consequence

MED13L
NM_015335.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.79

Variant links:

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 links:

MED13L (HGNC:):

MED13L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED13L. . Gene score misZ 3.691 (greater than the threshold 3.09). Trascript score misZ 6.2821 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, congenital heart disease, cardiac anomalies - developmental delay - facial dysmorphism syndrome.

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED13L	NM_015335.5 linkuse as main transcript	c.4744T>A	p.Ser1582Thr	missense_variant	21/31	ENST00000281928.9	NP_056150.1	Q71F56

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED13L	ENST00000281928.9 linkuse as main transcript	c.4744T>A	p.Ser1582Thr	missense_variant	21/31	1	NM_015335.5	ENSP00000281928.3		Q71F56

Frequencies

GnomAD3 genomes

AF:

0.00794

AC:

1208

AN:

152208

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00178

AC XY:

242

AN XY:

135784

show subpopulations

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.:

Cov.:

AF XY:

0.000795

AC XY:

578

AN XY:

727234

show subpopulations

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.:

Cov.:

AF XY:

0.00766

AC XY:

571

AN XY:

74496

show subpopulations

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.:

Bravo

AF:

0.00957

ESP6500AA

AF:

0.0232

AC:

102

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00278

AC:

337

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

MED13L-related disorder

Benign:1

Benign, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.39

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over