19-16576499-C-G

Variant names:

• chr19-16576499-C-G
• rs747945163
• NM_004831.5:c.1331G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_004831.5(MED26):​c.1331G>C​(p.Arg444Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,866 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MED26 NM_004831.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.789

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16114822).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED26	NM_004831.5	c.1331G>C	p.Arg444Pro	missense_variant	Exon 3 of 3	ENST00000263390.8	NP_004822.2
LOC105372295	XR_936359.3	n.475-1667C>G		intron_variant	Intron 1 of 2
LOC105372295	XR_936360.3	n.260-1667C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED26	ENST00000263390.8	c.1331G>C	p.Arg444Pro	missense_variant	Exon 3 of 3	1	NM_004831.5	ENSP00000263390.3
MED26	ENST00000611692	c.*696G>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000484490.1
ENSG00000141979	ENST00000409035.1	n.1211+144G>C		intron_variant	Intron 4 of 11	2		ENSP00000386951.2
MED26	ENST00000597244.1	n.2279G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.078
Sift	Uncertain	0.019	D
Sift4G	Benign	0.34	T
Polyphen		0.91	P
Vest4		0.24
MutPred		0.15		Loss of MoRF binding (P = 0.0361);
MVP		0.14
MPC		0.83
ClinPred		0.59	D
GERP RS		-1.3
Varity_R		0.24
gMVP		0.075

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

LitVar

Other links and lift over

dbSNP: rs747945163; hg19: chr19-16687310;