17-39407701-A-C

Position:

• chr17-39407701-A-C

Variant summary

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

The NM_004774.4(MED1):​c.4520T>G​(p.Val1507Gly) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

MED1 (HGNC:9234): (mediator complex subunit 1) 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. It also regulates p53-dependent apoptosis and it is essential for adipogenesis. This protein is known to have the ability to self-oligomerize. [provided by RefSeq, Jul 2008]

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=0.11388236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED1	NM_004774.4	c.4520T>G	p.Val1507Gly	missense_variant	17/17	ENST00000300651.11	NP_004765.2
MED1	XM_047436314.1	c.4004T>G	p.Val1335Gly	missense_variant	13/13		XP_047292270.1
MED1	XM_047436315.1	c.3863T>G	p.Val1288Gly	missense_variant	9/9		XP_047292271.1
MED1	XM_006721957.3	c.1641-2492T>G		intron_variant			XP_006722020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED1	ENST00000300651.11	c.4520T>G	p.Val1507Gly	missense_variant	17/17	1	NM_004774.4	ENSP00000300651.6
MED1	ENST00000394287.7	c.1641-2393T>G		intron_variant		1		ENSP00000377828.3
MED1	ENST00000577831.5	n.*4093T>G		downstream_gene_variant		2		ENSP00000463307.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

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

May 08, 2024

The c.4520T>G (p.V1507G) alteration is located in exon 17 (coding exon 17) of the MED1 gene. This alteration results from a T to G substitution at nucleotide position 4520, causing the valine (V) at amino acid position 1507 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.080
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.039
Sift	Uncertain	0.015	D
Sift4G	Benign	0.36	T
Polyphen		0.31	B
Vest4		0.18
MutPred		0.29		Loss of stability (P = 0.0348);
MVP		0.18
MPC		0.35
ClinPred		0.33	T
GERP RS		5.2
Varity_R		0.21
gMVP		0.11

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: chr17-37563954;