17-39407716-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_004774.4(MED1):c.4505A>G(p.Lys1502Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,614,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: MED1 NM_004774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

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 -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MED1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17436197).
• BS2: High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED1	NM_004774.4	c.4505A>G	p.Lys1502Arg	missense_variant	17/17	ENST00000300651.11
MED1	XM_047436314.1	c.3989A>G	p.Lys1330Arg	missense_variant	13/13
MED1	XM_047436315.1	c.3848A>G	p.Lys1283Arg	missense_variant	9/9
MED1	XM_006721957.3	c.1641-2507A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED1	ENST00000300651.11	c.4505A>G	p.Lys1502Arg	missense_variant	17/17	1	NM_004774.4	P1
MED1	ENST00000394287.7	c.1641-2408A>G		intron_variant		1
MED1	ENST00000577831.5	c.*4078A>G		3_prime_UTR_variant, NMD_transcript_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152220 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 250880 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135634

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000345 AC: 504 AN: 1461798 Hom.: 1 Cov.: 35 AF XY: 0.000362 AC XY: 263 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000424

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152338 Hom.: 0 Cov.: 31 AF XY: 0.000268 AC XY: 20 AN XY: 74500

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000296

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 09, 2021

The c.4505A>G (p.K1502R) alteration is located in exon 17 (coding exon 17) of the MED1 gene. This alteration results from a A to G substitution at nucleotide position 4505, causing the lysine (K) at amino acid position 1502 to be replaced by an arginine (R). 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	0.30
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.37
MVP		0.37
MPC		0.22
ClinPred		0.18	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.17

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: rs187579593; hg19: chr17-37563969;