rs150007121

Positions:

• chr8-100187243-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_003114.5(SPAG1):​c.825C>T​(p.Asn275Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,604,630 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: SPAG1 NM_003114.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0870

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 -12 ACMG points.

• BP6: Variant 8-100187243-C-T is Benign according to our data. Variant chr8-100187243-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00133 (202/152070) while in subpopulation AFR AF= 0.00446 (185/41486). AF 95% confidence interval is 0.00393. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.825C>T	p.Asn275Asn	synonymous_variant	8/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.825C>T	p.Asn275Asn	synonymous_variant	8/19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4	c.825C>T	p.Asn275Asn	synonymous_variant	8/19	5		ENSP00000251809.3
SPAG1	ENST00000520508.5	c.825C>T	p.Asn275Asn	synonymous_variant	8/10	5		ENSP00000428070.1
SPAG1	ENST00000520643.5	c.825C>T	p.Asn275Asn	synonymous_variant	8/10	2		ENSP00000427716.1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 151954 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000365 AC: 90 AN: 246504 Hom.: 0 AF XY: 0.000248 AC XY: 33 AN XY: 133330

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.000451

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.0000680

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000164 AC: 238 AN: 1452560 Hom.: 1 Cov.: 29 AF XY: 0.000137 AC XY: 99 AN XY: 722628

Gnomad4 AFR exome AF: 0.00477

Gnomad4 AMR exome AF: 0.000528

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.0000591

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.000668

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152070 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74324

Gnomad4 AFR AF: 0.00446

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000525 Hom.: 1

Bravo AF: 0.00152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 28 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.5
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs150007121; hg19: chr8-101199471;