rs1135401765

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_015335.5(MED13L):​c.5173C>T​(p.Gln1725*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

MED13L
NM_015335.5 stop_gained, splice_region

Scores

5
1
1
Splicing: ADA: 0.9998
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.60
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-115982386-G-A is Pathogenic according to our data. Variant chr12-115982386-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 431108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-115982386-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MED13LNM_015335.5 linkc.5173C>T p.Gln1725* stop_gained, splice_region_variant 22/31 ENST00000281928.9 NP_056150.1 Q71F56

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MED13LENST00000281928.9 linkc.5173C>T p.Gln1725* stop_gained, splice_region_variant 22/311 NM_015335.5 ENSP00000281928.3 Q71F56

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinAug 31, 2021ACMG classification criteria: PVS1, PS4, PM2, PM6 -
Cardiac anomalies - developmental delay - facial dysmorphism syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergAug 01, 2017De novo LOF variant in a patient with moderate ID, attention difficulties, strabismus, hypotonia, cryptorchidism. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
52
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
1.0
D
Vest4
0.43
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.51
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.51
Position offset: -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.

Other links and lift over

dbSNP: rs1135401765; hg19: chr12-116420191; API