rs372481440

Variant names:

• chr1-43384498-C-G
• rs372481440
• NM_201542.5:c.*544G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-43384498-C-G
• chr1-43384498-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052877.5(MED8):​c.858G>C​(p.Lys286Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MED8 NM_052877.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.844
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05559069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052877.5. 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
	MED8	NM_201542.5	MANE Select	c.*544G>C		3_prime_UTR	Exon 7 of 7	NP_963836.2	Q96G25-1
	MED8	NM_052877.5		c.858G>C	p.Lys286Asn	missense	Exon 8 of 8	NP_443109.2	Q96G25-2
	MED8	NM_001001653.3		c.*544G>C		3_prime_UTR	Exon 7 of 7	NP_001001653.1	Q96G25-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED8	ENST00000372457.9	TSL:2 MANE Select	c.*544G>C		3_prime_UTR	Exon 7 of 7	ENSP00000361535.4	Q96G25-1
	MED8	ENST00000290663.10	TSL:5	c.858G>C	p.Lys286Asn	missense	Exon 8 of 8	ENSP00000290663.6	Q96G25-2
	MED8	ENST00000939322.1		c.*544G>C		3_prime_UTR	Exon 7 of 7	ENSP00000609381.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246542 AF XY: 0.00000751

Gnomad AFR exome AF: 0.0000640

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459294 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725592

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110830

Other (OTH) AF: 0.0000995 AC: 6 AN: 60310

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74444

African (AFR) AF: 0.000168 AC: 7 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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	Benign	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.4
DANN	Benign	0.96
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.84
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.027	B
Vest4		0.11
MutPred		0.21		Loss of methylation at K286 (P = 0.0231)
MVP		0.23
MPC		0.36
ClinPred		0.56	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.18
Mutation Taster		=100/0	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: rs372481440; hg19: chr1-43850169;