12-115991442-T-G

Position:

• chr12-115991442-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000281928.9(MED13L):​c.3512A>C​(p.Lys1171Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1171R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED13L ENST00000281928.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.35144258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED13L	NM_015335.5	c.3512A>C	p.Lys1171Thr	missense_variant	17/31	ENST00000281928.9	NP_056150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED13L	ENST00000281928.9	c.3512A>C	p.Lys1171Thr	missense_variant	17/31	1	NM_015335.5	ENSP00000281928	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;.
Sift4G	Benign	0.087	T;.
Polyphen		0.28	B;.
Vest4		0.47
MutPred		0.46		Gain of catalytic residue at L1172 (P = 0);Gain of catalytic residue at L1172 (P = 0);
MVP		0.40
MPC		0.72
ClinPred		0.67	D
GERP RS		4.2
Varity_R		0.15
gMVP		0.84

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: rs147863200; hg19: chr12-116429247; COSMIC: COSV56130680;