chr17-39409270-G-A
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
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
NM_004774.4 missense
Scores
5
14
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.054616123).
BS2
High AC in GnomAd4 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: 21AN: 152090Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251416Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135896
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461890Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 727246
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74422
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at