8-100213331-C-G

Position:

• chr8-100213331-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003114.5(SPAG1):​c.1338C>G​(p.Ala446Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,311,082 control chromosomes in the GnomAD database, including 85,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8831 hom., cov: 32)
  • Exomes 𝑓: 0.36 (76848 hom.)
• Consequence: SPAG1 NM_003114.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.181

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-100213331-C-G is Benign according to our data. Variant chr8-100213331-C-G is described in ClinVar as [Benign]. Clinvar id is 262801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.181 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.1338C>G	p.Ala446Ala	synonymous_variant	11/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.1338C>G	p.Ala446Ala	synonymous_variant	11/19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4	c.1338C>G	p.Ala446Ala	synonymous_variant	11/19	5		ENSP00000251809.3
SPAG1	ENST00000523302.1	n.245C>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.331 AC: 49893 AN: 150894 Hom.: 8823 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.335

GnomAD3 exomes AF: 0.411 AC: 12927 AN: 31432 Hom.: 2806 AF XY: 0.405 AC XY: 7722 AN XY: 19064

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.528

Gnomad SAS exome AF: 0.356

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.361 AC: 419212 AN: 1160076 Hom.: 76848 Cov.: 33 AF XY: 0.362 AC XY: 203150 AN XY: 561644

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.493

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.340

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.331 AC: 49921 AN: 151006 Hom.: 8831 Cov.: 32 AF XY: 0.332 AC XY: 24536 AN XY: 73802

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.450

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.357

Gnomad4 OTH AF: 0.334

Alfa AF: 0.182 Hom.: 370

Bravo AF: 0.337

Asia WGS AF: 0.389 AC: 1349 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia 28 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 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	-0.41
CADD	Benign	6.8
DANN	Benign	0.59

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: rs2514681; hg19: chr8-101225559; COSMIC: COSV52557673;