rs148883126

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003114.5(SPAG1):c.2265A>T(p.Lys755Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,603,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.43

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026514143).

BP6

Variant 8-100239389-A-T is Benign according to our data. Variant chr8-100239389-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410995.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00132 (201/152310) while in subpopulation NFE AF = 0.00248 (169/68018). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.2265A>T	p.Lys755Asn	missense_variant	Exon 17 of 19	ENST00000388798.7	NP_003105.2	Q07617-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPAG1	ENST00000388798.7 link	c.2265A>T	p.Lys755Asn	missense_variant	Exon 17 of 19	1	NM_003114.5	ENSP00000373450.3	Q07617-1
SPAG1	ENST00000251809.4 link	c.2265A>T	p.Lys755Asn	missense_variant	Exon 17 of 19	5		ENSP00000251809.3	Q07617-1
SPAG1	ENST00000519424.1 link	n.517A>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

201

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00248

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00105

AC:

263

AN:

250746

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.000598

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00131

AC:

1902

AN:

1450790

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

963

AN XY:

722542

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33248

American (AMR)

AF:

0.000381

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85986

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00159

AC:

1747

AN:

1102126

Other (OTH)

AF:

0.000716

AC:

AN:

60022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

170

255

340

425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00132

AC:

201

AN:

152310

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00248

AC:

169

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00183

Hom.:

Bravo

AF:

0.000892

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00105

AC:

127

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:1

Apr 18, 2019

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Primary ciliary dyskinesia 28

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SPAG1-related disorder

Benign:1

Aug 19, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

T;.

M_CAP

Benign

0.026

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

1.4

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.21

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.97

D;D

Vest4

0.15

MutPred

0.26

Loss of ubiquitination at K755 (P = 0.0039);Loss of ubiquitination at K755 (P = 0.0039);

MVP

0.74

MPC

0.62

ClinPred

0.060

GERP RS

4.9

Varity_R

0.20

gMVP

0.22

Mutation Taster

=73/27

polymorphism

(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