Genetic Variant MEX3D:p.Arg532His (chr19-1555924-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_203304.4(MEX3D):c.1595G>A(p.Arg532His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000921 in 1,193,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

MEX3D
NM_203304.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

Variant links:

Genes affected

MEX3D (HGNC:16734): (mex-3 RNA binding family member D) Enables mRNA 3'-UTR AU-rich region binding activity. Located in nucleus and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MEX3D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MEX3D	NM_203304.4 link	c.1595G>A	p.Arg532His	missense_variant	Exon 2 of 2	ENST00000402693.5	NP_976049.3	Q86XN8-1
MEX3D	NM_001174118.2 link	c.1595G>A	p.Arg532His	missense_variant	Exon 2 of 3		NP_001167589.1	Q86XN8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEX3D	ENST00000402693.5 link	c.1595G>A	p.Arg532His	missense_variant	Exon 2 of 2	1	NM_203304.4	ENSP00000384398.3		Q86XN8-1
MEX3D	ENST00000605173.2 link	c.1067G>A	p.Arg356His	missense_variant	Exon 2 of 3	1		ENSP00000475059.1		S4R446

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

149404

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000670

AC:

AN:

1044360

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

494390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000155

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000497

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000446

Gnomad4 OTH exome

AF:

0.0000248

GnomAD4 genome

AF:

0.0000268

AC:

AN:

149404

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

72878

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1595G>A (p.R532H) alteration is located in exon 2 (coding exon 2) of the MEX3D gene. This alteration results from a G to A substitution at nucleotide position 1595, causing the arginine (R) at amino acid position 532 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.0059

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.63

T;T

M_CAP

Pathogenic

0.76

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.31

MutPred

0.27

Loss of methylation at R532 (P = 0.0288);.;

MVP

0.51

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.71

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