17-39408091-T-G

Variant summary

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

The NM_004774.4(MED1):c.4130A>C(p.Lys1377Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,846 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: 0.0000021 (0 hom.)
• Consequence: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

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=0.34894508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED1	NM_004774.4	c.4130A>C	p.Lys1377Thr	missense_variant	17/17	ENST00000300651.11
MED1	XM_047436314.1	c.3614A>C	p.Lys1205Thr	missense_variant	13/13
MED1	XM_047436315.1	c.3473A>C	p.Lys1158Thr	missense_variant	9/9
MED1	XM_006721957.3	c.1640+2490A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED1	ENST00000300651.11	c.4130A>C	p.Lys1377Thr	missense_variant	17/17	1	NM_004774.4	P1
MED1	ENST00000394287.7	c.1640+2490A>C		intron_variant		1
MED1	ENST00000577831.5	c.*3703A>C		3_prime_UTR_variant, NMD_transcript_variant	16/16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461846 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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 16, 2023

The c.4130A>C (p.K1377T) alteration is located in exon 17 (coding exon 17) of the MED1 gene. This alteration results from a A to C substitution at nucleotide position 4130, causing the lysine (K) at amino acid position 1377 to be replaced by a threonine (T). 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	0.41
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.40		Loss of ubiquitination at K1377 (P = 0.0059);
MVP		0.29
MPC		0.33
ClinPred		0.81	D
GERP RS		4.2
Varity_R		0.086
gMVP		0.33

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: chr17-37564344;