rs56246127

Positions:

• chr8-100194231-A-AGAC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003114.5(SPAG1):​c.1059_1060insGAC​(p.Lys353_Ser354insAsp) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,603,786 control chromosomes in the GnomAD database, including 32,931 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2435 hom., cov: 29)
  • Exomes 𝑓: 0.20 (30496 hom.)
• Consequence: SPAG1 NM_003114.5 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.19

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 -16 ACMG points.

• BP6: Variant 8-100194231-A-AGAC is Benign according to our data. Variant chr8-100194231-A-AGAC is described in ClinVar as [Benign]. Clinvar id is 221008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.1059_1060insGAC	p.Lys353_Ser354insAsp	inframe_insertion	10/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.1059_1060insGAC	p.Lys353_Ser354insAsp	inframe_insertion	10/19	1	NM_003114.5	ENSP00000373450	P1
SPAG1	ENST00000251809.4	c.1059_1060insGAC	p.Lys353_Ser354insAsp	inframe_insertion	10/19	5		ENSP00000251809	P1
SPAG1	ENST00000520508.5	c.1059_1060insGAC	p.Lys353_Ser354insAsp	inframe_insertion	10/10	5		ENSP00000428070
SPAG1	ENST00000520643.5	c.1059_1060insGAC	p.Lys353_Ser354insAsp	inframe_insertion	10/10	2		ENSP00000427716

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25464 AN: 152052 Hom.: 2438 Cov.: 29

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0717

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.194 AC: 48036 AN: 248246 Hom.: 5161 AF XY: 0.199 AC XY: 26655 AN XY: 134236

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.0536

Gnomad SAS exome AF: 0.242

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.200 AC: 289875 AN: 1451616 Hom.: 30496 Cov.: 29 AF XY: 0.201 AC XY: 145532 AN XY: 722402

Gnomad4 AFR exome AF: 0.0646

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.0784

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.167 AC: 25459 AN: 152170 Hom.: 2435 Cov.: 29 AF XY: 0.169 AC XY: 12545 AN XY: 74368

Gnomad4 AFR AF: 0.0746

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0717

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.184

Alfa AF: 0.203 Hom.: 579

Bravo AF: 0.157

Asia WGS AF: 0.149 AC: 520 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 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. -

Primary ciliary dyskinesia 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56246127; hg19: chr8-101206459; COSMIC: COSV52558023;