rs144410580

Positions:

• chr12-116009130-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_015335.5(MED13L):​c.1283A>G​(p.His428Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00177 in 1,613,982 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (18 hom.)
• Consequence: MED13L NM_015335.5 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.63

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MED13L
• BP4: Computational evidence support a benign effect (MetaRNN=0.009149104).
• BP6: Variant 12-116009130-T-C is Benign according to our data. Variant chr12-116009130-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 376878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-116009130-T-C is described in Lovd as [Likely_benign]. Variant chr12-116009130-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13L	NM_015335.5	c.1283A>G	p.His428Arg	missense_variant, splice_region_variant	10/31	ENST00000281928.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13L	ENST00000281928.9	c.1283A>G	p.His428Arg	missense_variant, splice_region_variant	10/31	1	NM_015335.5	P1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00275 AC: 687 AN: 250022 Hom.: 6 AF XY: 0.00265 AC XY: 359 AN XY: 135502

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00174 AC: 2544 AN: 1461710 Hom.: 18 Cov.: 32 AF XY: 0.00173 AC XY: 1258 AN XY: 727150

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74458

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.000536

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00290 AC: 352

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MED13L: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.070	T;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.044	D;.;.;.
Sift4G	Benign	0.082	T;.;.;.
Polyphen		0.96	D;.;.;.
Vest4		0.55
MVP		0.34
MPC		0.18
ClinPred		0.052	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.31

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: rs144410580; hg19: chr12-116446935;