Variant summary

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

The NM_003114.5(SPAG1):c.1307C>T(p.Pro436Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,232,072 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P436Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.227

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=0.00391227).

BP6

Variant 8-100213300-C-T is Benign according to our data. Variant chr8-100213300-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474651.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (194/150416) while in subpopulation NFE AF = 0.00252 (170/67348). AF 95% confidence interval is 0.00221. There are 1 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003114.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPAG1	NM_003114.5	MANE Select	c.1307C>T	p.Pro436Leu	missense	Exon 11 of 19	NP_003105.2
SPAG1	NM_001374321.1		c.1307C>T	p.Pro436Leu	missense	Exon 11 of 19	NP_001361250.1
SPAG1	NM_172218.3		c.1307C>T	p.Pro436Leu	missense	Exon 11 of 19	NP_757367.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.1307C>T	p.Pro436Leu	missense	Exon 11 of 19	ENSP00000373450.3
SPAG1	ENST00000251809.4	TSL:5	c.1307C>T	p.Pro436Leu	missense	Exon 11 of 19	ENSP00000251809.3
SPAG1	ENST00000523302.1	TSL:3	n.214C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

194

AN:

150308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00252

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.00167

AC:

AN:

3600

AF XY:

0.00220

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00524

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00133

AC:

1442

AN:

1081656

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

720

AN XY:

515090

show subpopulations

African (AFR)

AF:

0.0000894

AC:

AN:

22364

American (AMR)

AF:

0.00

AC:

AN:

8060

Ashkenazi Jewish (ASJ)

AF:

0.00217

AC:

AN:

13802

East Asian (EAS)

AF:

0.00

AC:

AN:

25736

South Asian (SAS)

AF:

0.00143

AC:

AN:

20268

European-Finnish (FIN)

AF:

0.00130

AC:

AN:

23774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2908

European-Non Finnish (NFE)

AF:

0.00141

AC:

1303

AN:

921868

Other (OTH)

AF:

0.00110

AC:

AN:

42876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.00129

AC:

194

AN:

150416

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

73452

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41354

American (AMR)

AF:

0.000198

AC:

AN:

15142

Ashkenazi Jewish (ASJ)

AF:

0.00290

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.000623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00252

AC:

170

AN:

67348

Other (OTH)

AF:

0.00144

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.00281

Hom.:

Bravo

AF:

0.000986

ExAC

AF:

0.000461

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (1)

Primary ciliary dyskinesia 28 (1)

SPAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.012

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-0.23

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.39

REVEL

Benign

0.025

Sift

Benign

0.45

Sift4G

Benign

0.21

Polyphen

0.049

Vest4

0.14

MVP

0.49

MPC

0.15

ClinPred

0.022

GERP RS

-0.89

Varity_R

0.025

gMVP

0.23

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over