rs17335870

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003114.5(SPAG1):c.991G>A(p.Glu331Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,596,798 control chromosomes in the GnomAD database, including 32,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2459 hom., cov: 33)

Exomes 𝑓: 0.20 ( 30193 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.411

Publications

23 publications found

Variant links:

Genes affected

SPAG1 (HGNC:11212): (sperm associated antigen 1) The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein expressed by this gene is recognized by anti-sperm agglutinating antibodies from an infertile woman. Furthermore, immunization of female rats with the recombinant human protein reduced fertility. This protein localizes to the plasma membrane of germ cells in the testis and to the post-acrosomal plasma membrane of mature spermatozoa. Recombinant polypeptide binds GTP and exhibits GTPase activity. Thus, this protein may regulate GTP signal transduction pathways involved in spermatogenesis and fertilization. Two transcript variants of this gene encode the same protein. [provided by RefSeq, Jul 2008]

SPAG1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 28
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPAG1 links:

ENSG00000302563 (HGNC:):

ENSG00000302563 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002596289).

BP6

Variant 8-100194163-G-A is Benign according to our data. Variant chr8-100194163-G-A is described in ClinVar as Benign. ClinVar VariationId is 262805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.991G>A	p.Glu331Lys	missense_variant	Exon 10 of 19	ENST00000388798.7	NP_003105.2	Q07617-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7 link	c.991G>A	p.Glu331Lys	missense_variant	Exon 10 of 19	1	NM_003114.5	ENSP00000373450.3		Q07617-1

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25513

AN:

152040

Hom.:

2462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0746

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.0723

Gnomad SAS

AF:

0.229

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.188

AC:

45554

AN:

242126

AF XY:

0.193

show subpopulations

Gnomad AFR exome

AF:

0.0689

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.0522

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.201

Gnomad OTH exome

AF:

0.204

GnomAD4 exome

AF:

0.200

AC:

288370

AN:

1444638

Hom.:

30193

Cov.:

AF XY:

0.201

AC XY:

144427

AN XY:

718100

show subpopulations

African (AFR)

AF:

0.0639

AC:

2094

AN:

32760

American (AMR)

AF:

0.195

AC:

8226

AN:

42234

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

5669

AN:

25630

East Asian (EAS)

AF:

0.0782

AC:

3088

AN:

39488

South Asian (SAS)

AF:

0.238

AC:

19589

AN:

82136

European-Finnish (FIN)

AF:

0.253

AC:

13421

AN:

52960

Middle Eastern (MID)

AF:

0.239

AC:

1361

AN:

5696

European-Non Finnish (NFE)

AF:

0.202

AC:

223161

AN:

1104040

Other (OTH)

AF:

0.197

AC:

11761

AN:

59694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

10581

21162

31744

42325

52906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7688

15376

23064

30752

38440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.168

AC:

25508

AN:

152160

Hom.:

2459

Cov.:

AF XY:

0.169

AC XY:

12592

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0746

AC:

3097

AN:

41534

American (AMR)

AF:

0.180

AC:

2755

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

791

AN:

3472

East Asian (EAS)

AF:

0.0723

AC:

375

AN:

5186

South Asian (SAS)

AF:

0.228

AC:

1101

AN:

4828

European-Finnish (FIN)

AF:

0.248

AC:

2611

AN:

10540

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.209

AC:

14191

AN:

67984

Other (OTH)

AF:

0.184

AC:

390

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1076

2151

3227

4302

5378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.195

Hom.:

12401

Bravo

AF:

0.157

TwinsUK

AF:

0.198

AC:

736

ALSPAC

AF:

0.200

AC:

770

ESP6500AA

AF:

0.0756

AC:

333

ESP6500EA

AF:

0.200

AC:

1720

ExAC

AF:

0.195

AC:

23658

Asia WGS

AF:

0.149

AC:

520

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 28

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Jul 12, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.0

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.0091

.;T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.14

.;T;T;.

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

N;N;N;N

PhyloP100

0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

1.0

N;N;N;N

REVEL

Benign

0.073

Sift

Benign

0.94

T;T;T;T

Sift4G

Benign

0.84

T;T;T;T

Polyphen

0.0

.;B;.;B

Vest4

0.016

MPC

0.17

ClinPred

0.00022

GERP RS

-1.6

Varity_R

0.029

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over