1-28330730-T-C

Position:

• chr1-28330730-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017638.3(MED18):​c.68T>C​(p.Leu23Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MED18 NM_017638.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

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]

MED18 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED18	NM_017638.3	c.68T>C	p.Leu23Ser	missense_variant	2/3	ENST00000373842.9	NP_060108.2
MED18	NM_001127350.2	c.68T>C	p.Leu23Ser	missense_variant	2/3		NP_001120822.1
MED18	XM_005245914.5	c.68T>C	p.Leu23Ser	missense_variant	2/3		XP_005245971.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED18	ENST00000373842.9	c.68T>C	p.Leu23Ser	missense_variant	2/3	2	NM_017638.3	ENSP00000362948.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

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

Jun 10, 2024

The c.68T>C (p.L23S) alteration is located in exon 2 (coding exon 1) of the MED18 gene. This alteration results from a T to C substitution at nucleotide position 68, causing the leucine (L) at amino acid position 23 to be replaced by a serine (S). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.95	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.89		Gain of disorder (P = 0.0177);Gain of disorder (P = 0.0177);
MVP		0.40
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28657241;