17-39408088-G-T

Position:

• chr17-39408088-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_004774.4(MED1):​c.4133C>A​(p.Thr1378Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11419833).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED1	NM_004774.4	c.4133C>A	p.Thr1378Asn	missense_variant	17/17	ENST00000300651.11	NP_004765.2
MED1	XM_047436314.1	c.3617C>A	p.Thr1206Asn	missense_variant	13/13		XP_047292270.1
MED1	XM_047436315.1	c.3476C>A	p.Thr1159Asn	missense_variant	9/9		XP_047292271.1
MED1	XM_006721957.3	c.1640+2493C>A		intron_variant			XP_006722020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED1	ENST00000300651.11	c.4133C>A	p.Thr1378Asn	missense_variant	17/17	1	NM_004774.4	ENSP00000300651.6
MED1	ENST00000394287.7	c.1640+2493C>A		intron_variant		1		ENSP00000377828.3
MED1	ENST00000577831.5	n.*3706C>A		non_coding_transcript_exon_variant	16/16	2		ENSP00000463307.1
MED1	ENST00000577831.5	n.*3706C>A		3_prime_UTR_variant	16/16	2		ENSP00000463307.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461830 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Jul 14, 2024

The c.4133C>A (p.T1378N) alteration is located in exon 17 (coding exon 17) of the MED1 gene. This alteration results from a C to A substitution at nucleotide position 4133, causing the threonine (T) at amino acid position 1378 to be replaced by an asparagine (N). 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	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.013
Sift	Benign	0.17	T
Sift4G	Benign	0.46	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.36		Loss of phosphorylation at T1378 (P = 0.0092);
MVP		0.19
MPC		0.31
ClinPred		0.12	T
GERP RS		4.6
Varity_R		0.048
gMVP		0.058

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

LitVar

Other links and lift over

dbSNP: rs2048320157; hg19: chr17-37564341;