1-28330706-C-T

Variant names:

• chr1-28330706-C-T
• rs1649692414
• NM_017638.3:c.44C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017638.3(MED18):​c.44C>T​(p.Thr15Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MED18 NM_017638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27004832).

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.44C>T	p.Thr15Ile	missense	Exon 2 of 3	NP_060108.2	Q9BUE0
	MED18	NM_001127350.2		c.44C>T	p.Thr15Ile	missense	Exon 2 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.44C>T	p.Thr15Ile	missense	Exon 2 of 3	ENSP00000362948.4	Q9BUE0
	MED18	ENST00000398997.2	TSL:5	c.44C>T	p.Thr15Ile	missense	Exon 2 of 4	ENSP00000381963.2	Q9BUE0
	MED18	ENST00000474683.1	TSL:3	n.203C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450662 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721542

African (AFR) AF: 0.00 AC: 0 AN: 32802

American (AMR) AF: 0.0000236 AC: 1 AN: 42438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 38812

South Asian (SAS) AF: 0.00 AC: 0 AN: 84186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107594

Other (OTH) AF: 0.00 AC: 0 AN: 59974

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.010	N
REVEL	Benign	0.14
Sift	Benign	0.47	T
Sift4G	Benign	0.34	T
Polyphen		0.32	B
Vest4		0.62
MutPred		0.50		Loss of glycosylation at T15 (P = 0.0364)
MVP		0.23
MPC		0.58
ClinPred		0.41	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.28
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1649692414; hg19: chr1-28657217;