chr12-116019999-T-G

Variant names:

• chr12-116019999-T-G
• rs11611238
• NM_015335.5:c.626-27A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015335.5(MED13L):​c.626-27A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0957 in 1,588,040 control chromosomes in the GnomAD database, including 8,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.076 (556 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7752 hom.)
• Consequence: MED13L NM_015335.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0180
• 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-116019999-T-G is Benign according to our data. Variant chr12-116019999-T-G is described in ClinVar as Benign. ClinVar VariationId is 1263826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED13L	NM_015335.5	c.626-27A>C		intron_variant	Intron 5 of 30	ENST00000281928.9	NP_056150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED13L	ENST00000281928.9	c.626-27A>C		intron_variant	Intron 5 of 30	1	NM_015335.5	ENSP00000281928.3

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11526 AN: 152124 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.0772 AC: 19234 AN: 249132 AF XY: 0.0784

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0985

GnomAD4 exome AF: 0.0978 AC: 140403 AN: 1435798 Hom.: 7752 Cov.: 28 AF XY: 0.0962 AC XY: 68906 AN XY: 715970

African (AFR) AF: 0.0263 AC: 863 AN: 32856

American (AMR) AF: 0.0635 AC: 2831 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3124 AN: 25974

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39492

South Asian (SAS) AF: 0.0262 AC: 2243 AN: 85660

European-Finnish (FIN) AF: 0.0679 AC: 3621 AN: 53316

Middle Eastern (MID) AF: 0.146 AC: 831 AN: 5704

European-Non Finnish (NFE) AF: 0.111 AC: 121148 AN: 1088712

Other (OTH) AF: 0.0964 AC: 5736 AN: 59526

GnomAD4 genome AF: 0.0757 AC: 11525 AN: 152242 Hom.: 556 Cov.: 32 AF XY: 0.0712 AC XY: 5301 AN XY: 74430

African (AFR) AF: 0.0289 AC: 1200 AN: 41554

American (AMR) AF: 0.0764 AC: 1169 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4826

European-Finnish (FIN) AF: 0.0603 AC: 639 AN: 10602

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7636 AN: 67990

Other (OTH) AF: 0.106 AC: 224 AN: 2116

Alfa AF: 0.0977 Hom.: 1525

Bravo AF: 0.0772

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.8
DANN	Benign	0.71
PhyloP100		-0.018
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs11611238; hg19: chr12-116457804; COSMIC: COSV108026050;