rs137853118

Positions:

chr3-173019486-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

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:1U:1B:1

Conservation

PhyloP100: 2.52

Variant links:

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]

SPATA16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SPATA16	NM_031955.6 linkuse as main transcript	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/11	ENST00000351008.4	NP_114161.3	Q9BXB7A0A140VJV8
SPATA16	XM_006713778.4 linkuse as main transcript	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/11		XP_006713841.1
SPATA16	XM_017007308.3 linkuse as main transcript	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/9		XP_016862797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATA16	ENST00000351008.4 linkuse as main transcript	c.848G>A	p.Arg283Gln	missense_variant, splice_region_variant	4/11	1	NM_031955.6	ENSP00000341765.3		Q9BXB7

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

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:

AN:

251398

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135868

show subpopulations

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.:

Cov.:

AF XY:

0.000410

AC XY:

298

AN XY:

726808

show subpopulations

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:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74230

show subpopulations

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.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Globozoospermia

Pathogenic:1Uncertain: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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.015

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MVP

0.38

MPC

0.30

ClinPred

0.14

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

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