1-28330706-C-T

Position:

• chr1-28330706-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED18	NM_017638.3	c.44C>T	p.Thr15Ile	missense_variant	2/3	ENST00000373842.9	NP_060108.2
MED18	NM_001127350.2	c.44C>T	p.Thr15Ile	missense_variant	2/3		NP_001120822.1
MED18	XM_005245914.5	c.44C>T	p.Thr15Ile	missense_variant	2/3		XP_005245971.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED18	ENST00000373842.9	c.44C>T	p.Thr15Ile	missense_variant	2/3	2	NM_017638.3	ENSP00000362948	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000189

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

Jan 08, 2024

The c.44C>T (p.T15I) alteration is located in exon 2 (coding exon 1) of the MED18 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the threonine (T) at amino acid position 15 to be replaced by an isoleucine (I). 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	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;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;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.76	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.14
Sift	Benign	0.47	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.32	B;B
Vest4		0.62
MutPred		0.50		Loss of glycosylation at T15 (P = 0.0364);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1649692414; hg19: chr1-28657217;