12-116277092-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_015335.5(MED13L):c.40C>G(p.Leu14Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,944 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MED13L NM_015335.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MED13L

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13L	NM_015335.5	c.40C>G	p.Leu14Val	missense_variant	1/31	ENST00000281928.9
MED13L	XM_017019090.2	c.40C>G	p.Leu14Val	missense_variant	1/31
MED13L	XM_047428608.1	c.-125C>G		5_prime_UTR_variant	1/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13L	ENST00000281928.9	c.40C>G	p.Leu14Val	missense_variant	1/31	1	NM_015335.5	P1
MED13L	ENST00000650226.1	c.40C>G	p.Leu14Val	missense_variant	1/31
MED13L	ENST00000551197.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000473 AC: 1 AN: 211418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 115464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440944 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 714562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	0.0049
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.85	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.54	P;.
Vest4		0.38
MutPred		0.29		Gain of catalytic residue at G11 (P = 0.0086);Gain of catalytic residue at G11 (P = 0.0086);
MVP		0.72
MPC		0.98
ClinPred		0.28	T
GERP RS		1.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.23
gMVP		0.88

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: rs148454293; hg19: chr12-116714897;