rs35305781

chr8-100184628-G-Achr8-100184628-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003114.5(SPAG1):c.596G>A(p.Gly199Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000453 in 1,546,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G199A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	7/19	ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	7/19	1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	7/19	5		P1
SPAG1	ENST00000520508.5	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	7/10	5
SPAG1	ENST00000520643.5	c.596G>A	p.Gly199Asp	missense_variant, splice_region_variant	7/10	2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000191 AC: 4 AN: 208892 Hom.: 0 AF XY: 0.00000876 AC XY: 1 AN XY: 114198

Gnomad AFR exome AF: 0.000297

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1394632 Hom.: 0 Cov.: 26 AF XY: 0.00000144 AC XY: 1 AN XY: 695156

Gnomad4 AFR exome AF: 0.000136

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

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: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Benign	0.16	T;T;T;T
Polyphen		1.0	.;D;.;D
Vest4		0.56
MutPred		0.19		Loss of catalytic residue at A198 (P = 0.1019);Loss of catalytic residue at A198 (P = 0.1019);Loss of catalytic residue at A198 (P = 0.1019);Loss of catalytic residue at A198 (P = 0.1019);
MVP		0.90
MPC		0.73
ClinPred		0.69	D
GERP RS		5.6
Varity_R		0.46
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.040		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: rs35305781; hg19: chr8-101196856;