NM_003114.5:c.596G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_003114.5(SPAG1):c.596G>A(p.Gly199Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000453 in 1,546,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G199A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

SPAG1
NM_003114.5 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

Publications

5 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	Exon 7 of 19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SPAG1	ENST00000388798.7 link	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	Exon 7 of 19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4 link	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	Exon 7 of 19	5		ENSP00000251809.3
SPAG1	ENST00000520508.5 link	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	Exon 7 of 10	5		ENSP00000428070.1
SPAG1	ENST00000520643.5 link	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	Exon 7 of 10	2		ENSP00000427716.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000191

AC:

AN:

208892

AF XY:

0.00000876

show subpopulations

Gnomad AFR exome

AF:

0.000297

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000359

AC:

AN:

1394632

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

695156

show subpopulations

African (AFR)

AF:

0.000136

AC:

AN:

29492

American (AMR)

AF:

0.00

AC:

AN:

32904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24996

East Asian (EAS)

AF:

0.00

AC:

AN:

36400

South Asian (SAS)

AF:

0.00

AC:

AN:

77504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077108

Other (OTH)

AF:

0.00

AC:

AN:

57790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T;.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

.;T;T;.

M_CAP

Benign

0.054

MetaRNN

Benign

0.41

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.8

M;M;M;M

PhyloP100

4.8

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.022

D;D;D;D

Sift4G

Benign

0.16

T;T;T;T

Polyphen

1.0

.;D;.;D

Vest4

0.56

MutPred

0.19

Loss of catalytic residue at A198 (P = 0.1019);Loss of catalytic residue at A198 (P = 0.1019);Loss of catalytic residue at A198 (P = 0.1019);Loss of catalytic residue at A198 (P = 0.1019);

MVP

0.90

MPC

0.73

ClinPred

0.69

GERP RS

5.6

Varity_R

0.46

gMVP

0.40

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over