19-39392479-G-A

Position:

• chr19-39392479-G-A

Variant summary

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

The NM_017592.4(MED29):​c.232G>A​(p.Ala78Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED29 NM_017592.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

Genes affected

MED29 (HGNC:23074): (mediator complex subunit 29) MED29 is a subunit of the Mediator complex, a multiprotein coactivator of RNA transcription that interacts with DNA-bound transcriptional activators, RNA polymerase II (see MIM 180660), and general initiation factors (Sato et al., 2003 [PubMed 14576168]).[supplied by OMIM, Aug 2009]

MED29 (HGNC:):

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/exons	MANE	Protein	UniProt
MED29	NM_017592.4	c.232G>A	p.Ala78Thr	missense_variant	2/4	ENST00000315588.11	NP_060062.2
MED29	NM_001317770.3	c.232G>A	p.Ala78Thr	missense_variant	2/4		NP_001304699.2
MED29	NR_133915.3	n.261+841G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED29	ENST00000315588.11	c.232G>A	p.Ala78Thr	missense_variant	2/4	1	NM_017592.4	ENSP00000314343.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 27, 2024

The c.295G>A (p.A99T) alteration is located in exon 2 (coding exon 2) of the MED29 gene. This alteration results from a G to A substitution at nucleotide position 295, causing the alanine (A) at amino acid position 99 to be replaced by a threonine (T). 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	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	.;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	.;.;M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D;.;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.024	D;.;.;.;.
Sift4G	Benign	0.096	T;T;T;T;T
Polyphen		0.90	P;P;.;D;.
Vest4		0.88
MutPred		0.36		.;.;Gain of disorder (P = 0.1125);Gain of disorder (P = 0.1125);Gain of disorder (P = 0.1125);
MVP		0.62
MPC		0.59
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.35
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2078393669; hg19: chr19-39883119;