NM_015335.5:c.4744T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 16/21 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.79

Publications

3 publications found

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 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

MED13L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId is 241043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1214 AD gene.

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.4744T>A	p.Ser1582Thr	missense	Exon 21 of 31	NP_056150.1	Q71F56

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MED13L	ENST00000281928.9	TSL:1 MANE Select	c.4744T>A	p.Ser1582Thr	missense	Exon 21 of 31	ENSP00000281928.3	Q71F56
MED13L	ENST00000650226.1		c.4744T>A	p.Ser1582Thr	missense	Exon 21 of 31	ENSP00000496981.1	A0A3B3IRX3
MED13L	ENST00000649607.1		c.2926T>A	p.Ser976Thr	missense	Exon 12 of 22	ENSP00000497064.1	A0A3B3IS46

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

GnomAD2 exomes

AF:

0.00221

AC:

554

AN:

251246

AF XY:

0.00178

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 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

African (AFR)

AF:

0.0291

AC:

973

AN:

33480

American (AMR)

AF:

0.00309

AC:

138

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000917

AC:

102

AN:

1111996

Other (OTH)

AF:

0.00172

AC:

104

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00797

AC:

1214

AN:

152326

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

571

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0272

AC:

1132

AN:

41564

American (AMR)

AF:

0.00340

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68032

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

MED13L-related disorder (1)

TRANSPOSITION OF THE GREAT ARTERIES, DEXTRO-LOOPED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.029

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

PhyloP100

2.8

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.78

REVEL

Benign

0.091

Sift

Benign

0.66

Sift4G

Benign

0.19

Polyphen

0.0

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

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over