chr5-157139077-C-G

Position:

• chr5-157139077-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004270.5(MED7):​c.355G>C​(p.Val119Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MED7 NM_004270.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

Genes affected

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]

HAVCR2 (HGNC:18437): (hepatitis A virus cellular receptor 2) The protein encoded by this gene belongs to the immunoglobulin superfamily, and TIM family of proteins. CD4-positive T helper lymphocytes can be divided into types 1 (Th1) and 2 (Th2) on the basis of their cytokine secretion patterns. Th1 cells are involved in cell-mediated immunity to intracellular pathogens and delayed-type hypersensitivity reactions, whereas, Th2 cells are involved in the control of extracellular helminthic infections and the promotion of atopic and allergic diseases. This protein is a Th1-specific cell surface protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3692864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED7	NM_004270.5	c.355G>C	p.Val119Leu	missense_variant	2/2	ENST00000286317.6	NP_004261.1
MED7	NM_001100816.1	c.355G>C	p.Val119Leu	missense_variant	2/2		NP_001094286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED7	ENST00000286317.6	c.355G>C	p.Val119Leu	missense_variant	2/2	1	NM_004270.5	ENSP00000286317.5
MED7	ENST00000420343.1	c.355G>C	p.Val119Leu	missense_variant	2/2	2		ENSP00000401046.1
MED7	ENST00000524289.1	c.355G>C	p.Val119Leu	missense_variant	3/3	3		ENSP00000430746.1
HAVCR2	ENST00000524219.2	c.-294+3743G>C		intron_variant		4		ENSP00000430328.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2022

The c.355G>C (p.V119L) alteration is located in exon 2 (coding exon 1) of the MED7 gene. This alteration results from a G to C substitution at nucleotide position 355, causing the valine (V) at amino acid position 119 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N;N;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.55	T;T;.
Polyphen		0.012	B;B;.
Vest4		0.27
MutPred		0.36		Gain of catalytic residue at V119 (P = 0.1715);Gain of catalytic residue at V119 (P = 0.1715);Gain of catalytic residue at V119 (P = 0.1715);
MVP		0.50
MPC		0.37
ClinPred		0.79	D
GERP RS		5.9
Varity_R		0.16
gMVP		0.86

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-156566088;