Variant 4-17623721-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025205.5(MED28):c.460G>A(p.Ala154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

MED28
NM_025205.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.818

Variant links:

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]

MED28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018568963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED28	NM_025205.5 linkuse as main transcript	c.460G>A	p.Ala154Thr	missense_variant	4/4	ENST00000237380.12	NP_079481.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED28	ENST00000237380.12 linkuse as main transcript	c.460G>A	p.Ala154Thr	missense_variant	4/4	1	NM_025205.5	ENSP00000237380	P1
MED28	ENST00000503945.2 linkuse as main transcript	c.451G>A	p.Ala151Thr	missense_variant, NMD_transcript_variant	4/6	1		ENSP00000426529

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251352

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000649

AC:

949

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000612

AC XY:

445

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000792

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000374

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.460G>A (p.A154T) alteration is located in exon 4 (coding exon 4) of the MED28 gene. This alteration results from a G to A substitution at nucleotide position 460, causing the alanine (A) at amino acid position 154 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

Benign

0.066

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.0

DANN

Benign

0.96

DEOGEN2

Benign

0.091

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.82

M_CAP

Benign

0.0012

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.68

REVEL

Benign

0.070

Sift

Benign

0.13

Sift4G

Benign

0.39

Polyphen

0.0040

Vest4

0.041

MVP

0.32

MPC

0.034

ClinPred

0.015

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over