chr1-43388362-A-G

Variant names:

• chr1-43388362-A-G
• NM_201542.5:c.73T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_201542.5(MED8):​c.73T>C​(p.Ser25Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MED8 NM_201542.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

Genes affected

MED8 (HGNC:19971): (mediator complex subunit 8) This gene encodes a protein component of the mediator complex, which aids in transcriptional activation through interaction with RNA polymerase II and gene-specific transcription factors. The encoded protein may also function in ubiquitin ligation and protein degradation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

MED8-AS1 (HGNC:40908): (MED8 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED8	NM_201542.5	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 7	ENST00000372457.9	NP_963836.2
MED8	NM_052877.5	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 8		NP_443109.2
MED8	NM_001001653.3	c.-177T>C		5_prime_UTR_variant	Exon 2 of 7		NP_001001653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED8	ENST00000372457.9	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 7	2	NM_201542.5	ENSP00000361535.4
MED8	ENST00000372455.4	c.-177T>C		5_prime_UTR_variant	Exon 2 of 7	1		ENSP00000361533.4
MED8	ENST00000290663.10	c.73T>C	p.Ser25Pro	missense_variant	Exon 2 of 8	5		ENSP00000290663.6
MED8-AS1	ENST00000436713.1	n.282-344A>G		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461402 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73T>C (p.S25P) alteration is located in exon 2 (coding exon 2) of the MED8 gene. This alteration results from a T to C substitution at nucleotide position 73, causing the serine (S) at amino acid position 25 to be replaced by a proline (P). 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	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.37		Loss of stability (P = 0.0942);Loss of stability (P = 0.0942);
MVP		0.68
MPC		1.1
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.89

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: chr1-43854033;