Genetic Variant ZMAT5:p.Asp81Glu (chr22-29740678-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001003692.2(ZMAT5):c.243C>A(p.Asp81Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000081 in 1,604,468 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

ZMAT5
NM_001003692.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.223

Variant links:

Genes affected

ZMAT5 (HGNC:28046): (zinc finger matrin-type 5) Predicted to enable zinc ion binding activity. Predicted to be involved in RNA splicing. Located in nucleoplasm. Part of U12-type spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

ZMAT5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.0997501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMAT5	NM_001003692.2 link	c.243C>A	p.Asp81Glu	missense_variant	Exon 4 of 6	ENST00000344318.4	NP_001003692.1	Q9UDW3A0A024R1I1
ZMAT5	NM_001318129.2 link	c.243C>A	p.Asp81Glu	missense_variant	Exon 4 of 6		NP_001305058.1	Q9UDW3A0A024R1I1
ZMAT5	NM_019103.3 link	c.243C>A	p.Asp81Glu	missense_variant	Exon 5 of 7		NP_061976.1	Q9UDW3A0A024R1I1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMAT5	ENST00000344318.4 link	c.243C>A	p.Asp81Glu	missense_variant	Exon 4 of 6	1	NM_001003692.2	ENSP00000344241.3		Q9UDW3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000826

AC:

AN:

1452270

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

721176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

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:

0.00000993

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.243C>A (p.D81E) alteration is located in exon 5 (coding exon 3) of the ZMAT5 gene. This alteration results from a C to A substitution at nucleotide position 243, causing the aspartic acid (D) at amino acid position 81 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

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0038

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.72

M_CAP

Benign

0.0021

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.31

REVEL

Benign

0.053

Sift

Benign

0.52

Sift4G

Benign

1.0

Polyphen

0.028

Vest4

0.23

MutPred

0.25

Gain of helix (P = 0.0022);

MVP

0.085

ClinPred

0.10

GERP RS

2.8

Varity_R

0.028

gMVP

0.50

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