NM_003114.5:c.2598C>T

Variant names:

• chr8-100240720-C-T
• rs749696519
• NM_003114.5:c.2598C>T
• SPAG1 p.Pro866Pro

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6_ModerateBP7

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.325
• Publications: 0 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000132 — very rare for AD+AR gene (base 0.0001, raised to 0.00017 by highest known P/LP ClinVar AF 0.00017) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

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

Sel.	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:
	SPAG1 NM_172218.3		c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: NP_757367.1 UniProt:

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

Sel.	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:
	SPAG1 ENST00000251809.4	TSL:5	c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: ENSP00000251809.3 UniProt:
	SPAG1 ENST00000964470.1		c.2598C>T p.Pro866Pro	synonymous	Exon 18 of 19	Prot: ENSP00000634529.1 UniProt:

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
	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

Pathogenic	VUS	Benign	Condition
-	-	1	Primary ciliary dyskinesia 28 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
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.

Other links and lift over

dbSNP: rs749696519;

hg19: chr8-101252948;

COSMIC: COSV52558508;

COSMIC: COSV52558508;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar