4-176188178-T-C

Variant names:

• chr4-176188178-T-C
• rs1208027100
• NM_144644.4:c.746A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144644.4(SPATA4):​c.746A>G​(p.Gln249Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 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 0.0000066 (0 hom., cov: 32)
• Consequence: SPATA4 NM_144644.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.204

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]

ACMG classification

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=0.062463075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATA4	NM_144644.4	c.746A>G	p.Gln249Arg	missense_variant	Exon 5 of 6	ENST00000280191.7	NP_653245.2
SPATA4	XM_047449608.1	c.227A>G	p.Gln76Arg	missense_variant	Exon 5 of 6		XP_047305564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA4	ENST00000280191.7	c.746A>G	p.Gln249Arg	missense_variant	Exon 5 of 6	1	NM_144644.4	ENSP00000280191.2
SPATA4	ENST00000515234.1	c.227A>G	p.Gln76Arg	missense_variant	Exon 4 of 5	1		ENSP00000422290.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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 Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746A>G (p.Q249R) alteration is located in exon 5 (coding exon 5) of the SPATA4 gene. This alteration results from a A to G substitution at nucleotide position 746, causing the glutamine (Q) at amino acid position 249 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	0.070
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.48
DANN	Benign	0.96
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.022
Sift	Benign	0.32	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;.
Vest4		0.048
MutPred		0.22		Gain of MoRF binding (P = 0.0239);.;
MVP		0.36
MPC		0.10
ClinPred		0.11	T
GERP RS		2.2
Varity_R		0.054
gMVP		0.22

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

Other links and lift over

dbSNP: rs1208027100; hg19: chr4-177109329;