rs61936939

Variant names:

• chr12-115969105-G-A
• rs61936939
• NM_015335.5:c.6068-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015335.5(MED13L):​c.6068-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,354 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (206 hom.)
• Consequence: MED13L NM_015335.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005156
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0630
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-115969105-G-A is Benign according to our data. Variant chr12-115969105-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0141 (20659/1461180) while in subpopulation NFE AF = 0.016 (17752/1111604). AF 95% confidence interval is 0.0158. There are 206 homozygotes in GnomAdExome4. There are 10147 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1603 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.6068-8C>T		splice_region intron	N/A	NP_056150.1	Q71F56

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED13L	ENST00000281928.9	TSL:1 MANE Select	c.6068-8C>T		splice_region intron	N/A	ENSP00000281928.3	Q71F56
	MED13L	ENST00000650226.1		c.6104-8C>T		splice_region intron	N/A	ENSP00000496981.1	A0A3B3IRX3
	MED13L	ENST00000649607.1		c.4250-8C>T		splice_region intron	N/A	ENSP00000497064.1	A0A3B3IS46

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1603 AN: 152056 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00300

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0106 AC: 2657 AN: 250018 AF XY: 0.0108

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00678

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0141 AC: 20659 AN: 1461180 Hom.: 206 Cov.: 32 AF XY: 0.0140 AC XY: 10147 AN XY: 726886

African (AFR) AF: 0.00224 AC: 75 AN: 33460

American (AMR) AF: 0.0105 AC: 468 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 150 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00540 AC: 466 AN: 86228

European-Finnish (FIN) AF: 0.0159 AC: 846 AN: 53362

Middle Eastern (MID) AF: 0.00403 AC: 23 AN: 5702

European-Non Finnish (NFE) AF: 0.0160 AC: 17752 AN: 1111604

Other (OTH) AF: 0.0145 AC: 878 AN: 60360

GnomAD4 genome AF: 0.0105 AC: 1603 AN: 152174 Hom.: 13 Cov.: 32 AF XY: 0.0106 AC XY: 787 AN XY: 74404

African (AFR) AF: 0.00299 AC: 124 AN: 41524

American (AMR) AF: 0.0147 AC: 225 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.0156 AC: 165 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1025 AN: 67988

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0124 Hom.: 9

Bravo AF: 0.0103

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Intellectual disability (1)
-	-	1	TRANSPOSITION OF THE GREAT ARTERIES, DEXTRO-LOOPED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.38
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs61936939; hg19: chr12-116406910;