17-39409660-G-A

Variant names:

• chr17-39409660-G-A
• NM_004774.4:c.2561C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004774.4(MED1):​c.2561C>T​(p.Pro854Leu) variant causes a missense change involving the alteration of a 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: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25730294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED1	NM_004774.4	c.2561C>T	p.Pro854Leu	missense_variant	Exon 17 of 17	ENST00000300651.11	NP_004765.2
MED1	XM_047436314.1	c.2045C>T	p.Pro682Leu	missense_variant	Exon 13 of 13		XP_047292270.1
MED1	XM_047436315.1	c.1904C>T	p.Pro635Leu	missense_variant	Exon 9 of 9		XP_047292271.1
MED1	XM_006721957.3	c.1640+921C>T		intron_variant	Intron 17 of 17		XP_006722020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED1	ENST00000300651.11	c.2561C>T	p.Pro854Leu	missense_variant	Exon 17 of 17	1	NM_004774.4	ENSP00000300651.6
MED1	ENST00000394287.7	c.1640+921C>T		intron_variant	Intron 17 of 17	1		ENSP00000377828.3
MED1	ENST00000577831.5	n.*2134C>T		non_coding_transcript_exon_variant	Exon 16 of 16	2		ENSP00000463307.1
MED1	ENST00000577831.5	n.*2134C>T		3_prime_UTR_variant	Exon 16 of 16	2		ENSP00000463307.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2561C>T (p.P854L) alteration is located in exon 17 (coding exon 17) of the MED1 gene. This alteration results from a C to T substitution at nucleotide position 2561, causing the proline (P) at amino acid position 854 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	Benign	0.13
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		10
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.029	D
Polyphen		0.82	P
Vest4		0.33
MutPred		0.39		Loss of relative solvent accessibility (P = 0.0306);
MVP		0.18
MPC		0.53
ClinPred		0.91	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.16

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

hg19: chr17-37565913;