1-28334872-G-T

Variant names:

• chr1-28334872-G-T
• rs139067472
• NM_017638.3:c.529G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017638.3(MED18):​c.529G>T​(p.Ala177Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A177T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MED18 NM_017638.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.87
• Publications: 0 publications found

Genes affected

MED18 (HGNC:25944): (mediator complex subunit 18) MED18 is a component of the Mediator complex, which is a coactivator for DNA-binding factors that activate transcription via RNA polymerase II (Sato et al., 2003 [PubMed 12584197]).[supplied by OMIM, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2625483).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017638.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED18	NM_017638.3	MANE Select	c.529G>T	p.Ala177Ser	missense	Exon 3 of 3	NP_060108.2	Q9BUE0
	MED18	NM_001127350.2		c.529G>T	p.Ala177Ser	missense	Exon 3 of 3	NP_001120822.1	Q9BUE0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED18	ENST00000373842.9	TSL:2 MANE Select	c.529G>T	p.Ala177Ser	missense	Exon 3 of 3	ENSP00000362948.4	Q9BUE0
	MED18	ENST00000398997.2	TSL:5	c.529G>T	p.Ala177Ser	missense	Exon 3 of 4	ENSP00000381963.2	Q9BUE0
	MED18	ENST00000479574.5	TSL:2	n.718G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251472 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		9.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.27
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Polyphen		0.49	P
Vest4		0.44
MutPred		0.37		Gain of disorder (P = 0.0249)
MVP		0.13
MPC		0.59
ClinPred		0.36	T
GERP RS		5.8
Varity_R		0.093
gMVP		0.36
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs139067472; hg19: chr1-28661383;