rs246869

Positions:

• chr5-157157373-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000524289.1(MED7):​c.-258+1511G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,108 control chromosomes in the GnomAD database, including 1,355 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1355 hom., cov: 31)
• Consequence: MED7 ENST00000524289.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131

Genes affected

ITK (HGNC:6171): (IL2 inducible T cell kinase) This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

MED7 (HGNC:2378): (mediator complex subunit 7) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITK	ENST00000521769.5	c.-296-8715C>T		intron_variant		4		ENSP00000430327
MED7	ENST00000524289.1	c.-258+1511G>A		intron_variant		3		ENSP00000430746

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19213 AN: 151990 Hom.: 1353 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.0902

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.121

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.126 AC: 19226 AN: 152108 Hom.: 1355 Cov.: 31 AF XY: 0.120 AC XY: 8949 AN XY: 74370

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0901

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0537

Gnomad4 FIN AF: 0.0902

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.120

Alfa AF: 0.140 Hom.: 194

Bravo AF: 0.128

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.7
DANN	Benign	0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs246869; hg19: chr5-156584384;