4-17614686-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025205.5(MED28):c.32G>A(p.Gly11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED28 NM_025205.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

Genes affected

MED28 (HGNC:24628): (mediator complex subunit 28) Predicted to enable actin binding activity. Predicted to act upstream of or within negative regulation of smooth muscle cell differentiation and stem cell population maintenance. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15359762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED28	NM_025205.5	c.32G>A	p.Gly11Glu	missense_variant	1/4	ENST00000237380.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED28	ENST00000237380.12	c.32G>A	p.Gly11Glu	missense_variant	1/4	1	NM_025205.5	P1
MED28	ENST00000503945.2	c.23G>A	p.Gly8Glu	missense_variant, NMD_transcript_variant	1/6	1
MED28	ENST00000506409.1	n.39G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461316 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

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.: 33

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

Oct 27, 2023

The c.32G>A (p.G11E) alteration is located in exon 1 (coding exon 1) of the MED28 gene. This alteration results from a G to A substitution at nucleotide position 32, causing the glycine (G) at amino acid position 11 to be replaced by a glutamic acid (E). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Benign	0.91
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.098
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.045	D
Polyphen		0.058	B
Vest4		0.43
MutPred		0.21		Loss of glycosylation at P16 (P = 0.0042);
MVP		0.48
MPC		0.043
ClinPred		0.59	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.59

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: chr4-17616309;