Genetic Variant SPATA4:p.His282Arg (chr4-176184853-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_144644.4(SPATA4):c.845A>G(p.His282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,600,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

SPATA4
NM_144644.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.141

Variant links:

Genes affected

SPATA4 (HGNC:17333): (spermatogenesis associated 4) Predicted to enable microtubule binding activity. Predicted to be involved in regulation of cytoskeleton organization. Predicted to be located in cytoplasm. Predicted to be active in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

SPATA4 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=0.061421245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATA4	NM_144644.4 link	c.845A>G	p.His282Arg	missense_variant	Exon 6 of 6	ENST00000280191.7	NP_653245.2	Q8NEY3
SPATA4	XM_047449608.1 link	c.326A>G	p.His109Arg	missense_variant	Exon 6 of 6		XP_047305564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA4	ENST00000280191.7 link	c.845A>G	p.His282Arg	missense_variant	Exon 6 of 6	1	NM_144644.4	ENSP00000280191.2		Q8NEY3
SPATA4	ENST00000515234.1 link	c.326A>G	p.His109Arg	missense_variant	Exon 5 of 5	1		ENSP00000422290.1		G5E9Y6

Frequencies

GnomAD3 genomes

AF:

0.000140

AC:

AN:

150250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000254

AC:

AN:

235908

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

127996

show subpopulations

Gnomad AFR exome

AF:

0.000386

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000896

AC:

AN:

1450742

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

721642

show subpopulations

Gnomad4 AFR exome

AF:

0.000364

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:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000140

AC:

AN:

150250

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

73386

show subpopulations

Gnomad4 AFR

AF:

0.000508

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845A>G (p.H282R) alteration is located in exon 6 (coding exon 6) of the SPATA4 gene. This alteration results from a A to G substitution at nucleotide position 845, causing the histidine (H) at amino acid position 282 to be replaced by an arginine (R). 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

0.071

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.2

DANN

Benign

0.79

DEOGEN2

Benign

0.0064

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.021

Sift

Benign

0.10

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.24

B;.

Vest4

0.19

MVP

0.47

MPC

0.14

ClinPred

0.022

GERP RS

0.94

Varity_R

0.050

gMVP

0.14

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

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