rs371427575

chr8-100177808-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_003114.5(SPAG1):c.301-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,448,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SPAG1 NM_003114.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003615
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0150

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 8-100177808-A-G is Benign according to our data. Variant chr8-100177808-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 416527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000315 (408/1296174) while in subpopulation MID AF= 0.00184 (10/5430). AF 95% confidence interval is 0.000999. There are 0 homozygotes in gnomad4_exome. There are 188 alleles in male gnomad4_exome subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.301-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.301-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.301-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		P1
SPAG1	ENST00000520508.5	c.301-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
SPAG1	ENST00000520643.5	c.301-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000388 AC: 85 AN: 219056 Hom.: 0 AF XY: 0.000363 AC XY: 43 AN XY: 118372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000661

Gnomad ASJ exome AF: 0.000970

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000569

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.000315 AC: 408 AN: 1296174 Hom.: 0 Cov.: 21 AF XY: 0.000289 AC XY: 188 AN XY: 650476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000646

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.000366

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74474

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000459 Hom.: 0

Bravo AF: 0.000393

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

VPS13B-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary ciliary dyskinesia 28 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	8.4
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.0080
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: rs371427575; hg19: chr8-101190036;