rs137853118

chr3-173019486-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_031955.6(SPATA16):c.848G>A(p.Arg283Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,612,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: SPATA16 NM_031955.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 2.52

Genes affected

SPATA16 (HGNC:29935): (spermatogenesis associated 16) This gene encodes a testis-specific protein that belongs to the tetratricopeptide repeat-like superfamily. The encoded protein localizes to the Golgi apparatus and may play a role in spermatogenesis. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-173019486-C-T is Benign according to our data. Variant chr3-173019486-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1411.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPATA16	NM_031955.6	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/11	ENST00000351008.4
SPATA16	XM_006713778.4	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/11
SPATA16	XM_017007308.3	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPATA16	ENST00000351008.4	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/11	1	NM_031955.6	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000306 AC: 77 AN: 251398 Hom.: 0 AF XY: 0.000353 AC XY: 48 AN XY: 135868

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000409 AC: 598 AN: 1460866 Hom.: 0 Cov.: 30 AF XY: 0.000410 AC XY: 298 AN XY: 726808

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000445

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74230

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Globozoospermia Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	The SPATA16 c.848G>A (p.Arg283Gln) variant is a missense variant that has been reported in a single study and is found in a homozygous state in three brothers from a consanguineous family affected with globozoospermia. Both the parents and two unaffected brothers were heterozygous for the variant (Dam et al. 2007). The p.Arg283Gln variant was absent from 231 control individuals and is reported at a frequency of 0.002856 in the Ashkenazi Jewish population of the Genome Aggregation Database. Three different splice-site prediction tools predicted the c.848G>A change to disrupt the splice site, and transfection of c.848G>A in COS1 or HeLa cells followed by RT-PCR showed aspecific mRNA products as a result of abnormal splicing. In addition, binding to the U1 small nuclear ribonucleoprotein (SnRNP) was evaluated; while the wild type DNA was found to bind to U1 SnRNP, binding could not be detected for the c.848G>A variant (Dam et al. 2007). CRISPR/Cas9-mediated R284Q mutant mice, which corresponded with R283Q variant in human SPATA16, was not found to affect male fertility; however, deletion of the fourth exon of Spata16 resulted in infertile male mice due to spermiogenic arrest but not globozoospermia (Fujihara et al. 2017). Based on the evidence, the p.Arg283Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for spermatogenic failure. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	36
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.77	A
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.38
MPC		0.30
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.54
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.80		Position offset: 18
DS_DL_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853118; hg19: chr3-172737276; COSMIC: COSV63527596;