rs61748072

Variant names:

• chr12-116019285-C-T
• rs61748072
• NM_015335.5:c.948G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015335.5(MED13L):​c.948G>A​(p.Lys316Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,902 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (200 hom.)
• Consequence: MED13L NM_015335.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.557
• Publications: 3 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, Illumina, Labcorp Genetics (formerly Invitae), G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-116019285-C-T is Benign according to our data. Variant chr12-116019285-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.557 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0137 (20097/1461680) while in subpopulation NFE AF = 0.0155 (17267/1111900). AF 95% confidence interval is 0.0153. There are 200 homozygotes in GnomAdExome4. There are 9831 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1543 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.948G>A	p.Lys316Lys	synonymous	Exon 7 of 31	NP_056150.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED13L	ENST00000281928.9	TSL:1 MANE Select	c.948G>A	p.Lys316Lys	synonymous	Exon 7 of 31	ENSP00000281928.3
	MED13L	ENST00000650226.1		c.948G>A	p.Lys316Lys	synonymous	Exon 7 of 31	ENSP00000496981.1
	MED13L	ENST00000549786.2	TSL:2	c.375G>A	p.Lys125Lys	synonymous	Exon 3 of 18	ENSP00000446782.2

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1543 AN: 152104 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.0105 AC: 2638 AN: 250916 AF XY: 0.0107

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0137 AC: 20097 AN: 1461680 Hom.: 200 Cov.: 31 AF XY: 0.0135 AC XY: 9831 AN XY: 727116

African (AFR) AF: 0.00221 AC: 74 AN: 33474

American (AMR) AF: 0.0101 AC: 453 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 151 AN: 26126

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

South Asian (SAS) AF: 0.00481 AC: 415 AN: 86256

European-Finnish (FIN) AF: 0.0159 AC: 849 AN: 53414

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5760

European-Non Finnish (NFE) AF: 0.0155 AC: 17267 AN: 1111900

Other (OTH) AF: 0.0143 AC: 863 AN: 60388

GnomAD4 genome AF: 0.0101 AC: 1543 AN: 152222 Hom.: 13 Cov.: 32 AF XY: 0.0101 AC XY: 752 AN XY: 74440

African (AFR) AF: 0.00296 AC: 123 AN: 41544

American (AMR) AF: 0.0137 AC: 210 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4828

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0145 AC: 987 AN: 68006

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.0124 Hom.: 9

Bravo AF: 0.00981

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0123

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.67
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61748072; hg19: chr12-116457090; COSMIC: COSV56119883;