rs1345608147

Variant names:

• chr19-16576673-G-A
• rs1345608147
• NM_004831.5:c.1157C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004831.5(MED26):​c.1157C>T​(p.Ser386Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MED26 NM_004831.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• Publications: 2 publications found

Genes affected

MED26 (HGNC:2376): (mediator complex subunit 26) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. [provided by RefSeq, Jul 2008]

ENSG00000141979 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17686695).
• BS2: High AC in GnomAdExome4 at 48 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004831.5. 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
	MED26	NM_004831.5	MANE Select	c.1157C>T	p.Ser386Leu	missense	Exon 3 of 3	NP_004822.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED26	ENST00000263390.8	TSL:1 MANE Select	c.1157C>T	p.Ser386Leu	missense	Exon 3 of 3	ENSP00000263390.3	O95402-1
	MED26	ENST00000611692.4	TSL:1	c.*522C>T		3_prime_UTR	Exon 4 of 4	ENSP00000484490.1	O95402-2
	ENSG00000141979	ENST00000409035.1	TSL:2	n.1181C>T		non_coding_transcript_exon	Exon 4 of 12	ENSP00000386951.2	B8ZZF3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250390 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461724 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.0000113

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	0.085
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.30	T
Polyphen		0.52	P
Vest4		0.12
MutPred		0.14		Loss of phosphorylation at S386 (P = 0.0013)
MVP		0.15
MPC		0.51
ClinPred		0.44	T
GERP RS		5.1
Varity_R		0.20
gMVP		0.15
Mutation Taster		=77/23	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: rs1345608147; hg19: chr19-16687484; COSMIC: COSV54659719; COSMIC: COSV54659719;