dbSNP rs749696519: SPAG1:p.Pro866Pro (chr8-100240720-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is The variant received -3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingB4_Strong

The NM_003114.5(SPAG1):c.2598C>T (p.Pro866Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000342 (AC=5) in the gnomAD database across 1,460,962 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000132. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SPAG1
NM_003114.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.325

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), G2P, PanelApp Australia, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPAG1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003114.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000001 — very rare (O3 supporting [+1])
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SPAG1 NM_003114.5	MANE Select	c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: NP_003105.2
SPAG1 NM_001374321.1		c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: NP_001361250.1 UniProt: Q07617-1
SPAG1 NM_172218.3		c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: NP_757367.1 UniProt: Q07617-1

SPAG1 NM_003114.5

MANE Select

HGVSc / HGVSpc.2598C>Tp.Pro866Pro

Exon rankExon 18 of 19

synonymous

Prot: NP_003105.2

SPAG1 NM_001374321.1

HGVSc / HGVSpc.2598C>Tp.Pro866Pro

Exon rankExon 18 of 19

synonymous

Prot: NP_001361250.1UniProt: Q07617-1

SPAG1 NM_172218.3

HGVSc / HGVSpc.2598C>Tp.Pro866Pro

Exon rankExon 18 of 19

synonymous

Prot: NP_757367.1UniProt: Q07617-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SPAG1 ENST00000388798.7	TSL:1MANE Select	c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: ENSP00000373450.3 UniProt: Q07617-1
SPAG1 ENST00000251809.4	TSL:5	c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: ENSP00000251809.3 UniProt: Q07617-1
SPAG1 ENST00000964470.1		c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: ENSP00000634529.1 UniProt: Q07617-1

SPAG1 ENST00000388798.7

TSL:1MANE Select

HGVSc / HGVSpc.2598C>Tp.Pro866Pro

Exon rankExon 18 of 19

synonymous

Prot: ENSP00000373450.3UniProt: Q07617-1

SPAG1 ENST00000251809.4

TSL:5

HGVSc / HGVSpc.2598C>Tp.Pro866Pro

Exon rankExon 18 of 19

synonymous

Prot: ENSP00000251809.3UniProt: Q07617-1

SPAG1 ENST00000964470.1

HGVSc / HGVSpc.2598C>Tp.Pro866Pro

Exon rankExon 18 of 19

synonymous

Prot: ENSP00000634529.1UniProt: Q07617-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000400	AC:1	Hom:	AN:250294	Cov:
GnomAD4 exome	AF: 0.00000342	AC:5	Hom:0	AN:1460962	Cov:36
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000612	AC:1	Hom:0	AN:16340	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
Cohort	AF	AC	AN	AF	AC	AN
Epi25 (Epilepsy)	0.0000238	1	41958	0.0000150	1	66878

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 28 (1)

Computational Scores

Algorithm	Calibrated pred.	Score
AlphaGenome AVI	Benign	4.3
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.7
DANN	Benign	0.33
GPN-Star LLR	N/A	-1.4
GPN-Star score	N/A	1.4
PhyloP100	Benign	-0.33

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Case/control cohorts

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence