13-48086375-A-T

Position:

• chr13-48086375-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014166.4(MED4):​c.270T>A​(p.His90Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MED4 NM_014166.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.919

Genes affected

MED4 (HGNC:17903): (mediator complex subunit 4) This gene encodes a component of the Mediator complex. The Mediator complex interacts with DNA-binding gene-specific transcription factors to modulate transcription by RNA polymerase II. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18211159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED4	NM_014166.4	c.270T>A	p.His90Gln	missense_variant	3/7	ENST00000258648.7	NP_054885.1
MED4	NM_001270629.2	c.132T>A	p.His44Gln	missense_variant	3/7		NP_001257558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED4	ENST00000258648.7	c.270T>A	p.His90Gln	missense_variant	3/7	1	NM_014166.4	ENSP00000258648	P1
MED4	ENST00000417167.2	c.204T>A	p.His68Gln	missense_variant	4/8	5		ENSP00000413595
MED4	ENST00000378586.5	c.132T>A	p.His44Gln	missense_variant	3/7	2		ENSP00000367849

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 19, 2024

The c.270T>A (p.H90Q) alteration is located in exon 3 (coding exon 3) of the MED4 gene. This alteration results from a T to A substitution at nucleotide position 270, causing the histidine (H) at amino acid position 90 to be replaced by a glutamine (Q). 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	Benign	0.29
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.052	T;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.14	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.23	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.37	T;T;.
Polyphen		0.062	B;.;.
Vest4		0.37
MutPred		0.42		Gain of catalytic residue at I89 (P = 0.011);.;.;
MVP		0.75
MPC		0.39
ClinPred		0.45	T
GERP RS		2.9
Varity_R		0.093
gMVP		0.57

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: chr13-48660511;