rs372464585

Variant names:

• chr12-116007641-A-G
• rs372464585
• NM_015335.5:c.2013-5T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015335.5(MED13L):​c.2013-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000919 in 1,544,510 control chromosomes in the GnomAD database, including 1 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 0.00054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: MED13L NM_015335.5 splice_region, intron
• Scores: Splicing: ADA: 0.002099
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.69
• Publications: 0 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-116007641-A-G is Benign according to our data. Variant chr12-116007641-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 533129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 80 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.2013-5T>C		splice_region intron	N/A	NP_056150.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED13L	ENST00000281928.9	TSL:1 MANE Select	c.2013-5T>C		splice_region intron	N/A	ENSP00000281928.3
	MED13L	ENST00000650226.1		c.2013-5T>C		splice_region intron	N/A	ENSP00000496981.1
	MED13L	ENST00000649607.1		c.198-5T>C		splice_region intron	N/A	ENSP00000497064.1

Frequencies

GnomAD3 genomes AF: 0.000542 AC: 80 AN: 147578 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000498

GnomAD2 exomes AF: 0.000123 AC: 27 AN: 219638 AF XY: 0.0000583

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.000143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.0000444 AC: 62 AN: 1396820 Hom.: 1 Cov.: 32 AF XY: 0.0000445 AC XY: 31 AN XY: 696282

African (AFR) AF: 0.00142 AC: 45 AN: 31626

American (AMR) AF: 0.000171 AC: 7 AN: 40944

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39032

South Asian (SAS) AF: 0.00 AC: 0 AN: 80186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1064500

Other (OTH) AF: 0.000138 AC: 8 AN: 57782

GnomAD4 genome AF: 0.000542 AC: 80 AN: 147690 Hom.: 0 Cov.: 30 AF XY: 0.000487 AC XY: 35 AN XY: 71904

African (AFR) AF: 0.00155 AC: 63 AN: 40576

American (AMR) AF: 0.00109 AC: 16 AN: 14728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4902

South Asian (SAS) AF: 0.00 AC: 0 AN: 4338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66742

Other (OTH) AF: 0.000493 AC: 1 AN: 2030

Alfa AF: 0.000379 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	13
DANN	Benign	0.58
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.010		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: rs372464585; hg19: chr12-116445446;