rs35252724

chr8-100220327-G-Achr8-100220327-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003114.5(SPAG1):c.1584G>A(p.Ala528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,614,090 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: SPAG1 NM_003114.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.408

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]

LOC105375669 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 8-100220327-G-A is Benign according to our data. Variant chr8-100220327-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00312 (476/152328) while in subpopulation AFR AF= 0.011 (459/41572). AF 95% confidence interval is 0.0102. There are 3 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.1584G>A	p.Ala528=	synonymous_variant	13/19	ENST00000388798.7
LOC105375669	XR_928450.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.1584G>A	p.Ala528=	synonymous_variant	13/19	1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.1584G>A	p.Ala528=	synonymous_variant	13/19	5		P1
SPAG1	ENST00000523302.1	n.343-4846G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 474 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000760 AC: 191 AN: 251304 Hom.: 3 AF XY: 0.000589 AC XY: 80 AN XY: 135812

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000309 AC: 452 AN: 1461762 Hom.: 4 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 727188

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.00312 AC: 476 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00282 AC XY: 210 AN XY: 74490

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000911 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 28 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 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	-0.50
Cadd	Benign	5.9
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35252724; hg19: chr8-101232555;