17-39408640-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004774.4(MED1):c.3581C>T(p.Ser1194Phe) 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: 31)
• Consequence: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.65

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MED1
• BP4: Computational evidence support a benign effect (MetaRNN=0.42331266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED1	NM_004774.4	c.3581C>T	p.Ser1194Phe	missense_variant	17/17	ENST00000300651.11
MED1	XM_047436314.1	c.3065C>T	p.Ser1022Phe	missense_variant	13/13
MED1	XM_047436315.1	c.2924C>T	p.Ser975Phe	missense_variant	9/9
MED1	XM_006721957.3	c.1640+1941C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED1	ENST00000300651.11	c.3581C>T	p.Ser1194Phe	missense_variant	17/17	1	NM_004774.4	P1
MED1	ENST00000394287.7	c.1640+1941C>T		intron_variant		1
MED1	ENST00000577831.5	c.*3154C>T		3_prime_UTR_variant, NMD_transcript_variant	16/16	2

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

Jan 30, 2024

The c.3581C>T (p.S1194F) 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 3581, causing the serine (S) at amino acid position 1194 to be replaced by a phenylalanine (F). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.35		Loss of phosphorylation at S1194 (P = 0.0016);
MVP		0.49
MPC		0.30
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.61

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: chr17-37564893;