rs35592493

Positions:

• chr8-100184701-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003114.5(SPAG1):​c.669A>G​(p.Gly223Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,588,374 control chromosomes in the GnomAD database, including 868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (300 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (568 hom.)
• Consequence: SPAG1 NM_003114.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.15

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-100184701-A-G is Benign according to our data. Variant chr8-100184701-A-G is described in ClinVar as [Benign]. Clinvar id is 416524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.669A>G	p.Gly223Gly	synonymous_variant	7/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.669A>G	p.Gly223Gly	synonymous_variant	7/19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4	c.669A>G	p.Gly223Gly	synonymous_variant	7/19	5		ENSP00000251809.3
SPAG1	ENST00000520508.5	c.669A>G	p.Gly223Gly	synonymous_variant	7/10	5		ENSP00000428070.1
SPAG1	ENST00000520643.5	c.669A>G	p.Gly223Gly	synonymous_variant	7/10	2		ENSP00000427716.1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5617 AN: 152136 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0206 AC: 4629 AN: 224248 Hom.: 179 AF XY: 0.0193 AC XY: 2353 AN XY: 121806

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.0996

Gnomad SAS exome AF: 0.0403

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00926 AC: 13292 AN: 1436120 Hom.: 568 Cov.: 29 AF XY: 0.00977 AC XY: 6975 AN XY: 714264

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.00481

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0391

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000631

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0370 AC: 5639 AN: 152254 Hom.: 300 Cov.: 32 AF XY: 0.0373 AC XY: 2781 AN XY: 74462

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.0999

Gnomad4 SAS AF: 0.0468

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0147 Hom.: 49

Bravo AF: 0.0412

Asia WGS AF: 0.0750 AC: 260 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2019	- -

Primary ciliary dyskinesia 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs35592493; hg19: chr8-101196929; COSMIC: COSV52560161; COSMIC: COSV52560161;