17-39409270-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_004774.4(MED1):c.2951C>T(p.Ser984Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MED1
• BP4: Computational evidence support a benign effect (MetaRNN=0.054616123).
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED1	NM_004774.4	c.2951C>T	p.Ser984Leu	missense_variant	17/17	ENST00000300651.11
MED1	XM_047436314.1	c.2435C>T	p.Ser812Leu	missense_variant	13/13
MED1	XM_047436315.1	c.2294C>T	p.Ser765Leu	missense_variant	9/9
MED1	XM_006721957.3	c.1640+1311C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED1	ENST00000300651.11	c.2951C>T	p.Ser984Leu	missense_variant	17/17	1	NM_004774.4	P1
MED1	ENST00000394287.7	c.1640+1311C>T		intron_variant		1
MED1	ENST00000577831.5	c.*2524C>T		3_prime_UTR_variant, NMD_transcript_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251416 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135896

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461890 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000629

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74422

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000167 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

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

Feb 05, 2024

The c.2951C>T (p.S984L) 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 2951, causing the serine (S) at amino acid position 984 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	0.084
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.75	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.052
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0040	B
Vest4		0.076
MVP		0.14
MPC		0.29
ClinPred		0.099	T
GERP RS		4.7
Varity_R		0.042
gMVP		0.057

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: rs146921601; hg19: chr17-37565523; COSMIC: COSV56124895; COSMIC: COSV56124895;