rs146528350

chr8-100194129-T-Achr8-100194129-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_003114.5(SPAG1):c.957T>A(p.Val319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,574,718 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (9 hom.)
• Consequence: SPAG1 NM_003114.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 8-100194129-T-A is Benign according to our data. Variant chr8-100194129-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 242017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-100194129-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000401 (61/152306) while in subpopulation SAS AF= 0.0031 (15/4832). AF 95% confidence interval is 0.00191. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.957T>A	p.Val319=	synonymous_variant	10/19	ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.957T>A	p.Val319=	synonymous_variant	10/19	1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.957T>A	p.Val319=	synonymous_variant	10/19	5		P1
SPAG1	ENST00000520508.5	c.957T>A	p.Val319=	synonymous_variant	10/10	5
SPAG1	ENST00000520643.5	c.957T>A	p.Val319=	synonymous_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000891 AC: 204 AN: 229002 Hom.: 1 AF XY: 0.00108 AC XY: 134 AN XY: 124010

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.000572

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000695 AC: 989 AN: 1422412 Hom.: 9 Cov.: 28 AF XY: 0.000795 AC XY: 562 AN XY: 706814

Gnomad4 AFR exome AF: 0.000348

Gnomad4 AMR exome AF: 0.000267

Gnomad4 ASJ exome AF: 0.000968

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.000470

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74478

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000465

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2016

This alteration is classified as likely 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

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	8.2
Dann	Benign	0.71

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: rs146528350; hg19: chr8-101206357;