8-100162368-A-G

Position:

• chr8-100162368-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_003114.5(SPAG1):​c.88A>G​(p.Ile30Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000757 in 1,598,092 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (1 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.14

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03484419).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000643 (93/1445728) while in subpopulation MID AF= 0.0021 (12/5710). AF 95% confidence interval is 0.00121. There are 1 homozygotes in gnomad4_exome. There are 46 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.88A>G	p.Ile30Val	missense_variant	2/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.88A>G	p.Ile30Val	missense_variant	2/19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4	c.88A>G	p.Ile30Val	missense_variant	2/19	5		ENSP00000251809.3
SPAG1	ENST00000520508.5	c.88A>G	p.Ile30Val	missense_variant	2/10	5		ENSP00000428070.1
SPAG1	ENST00000520643.5	c.88A>G	p.Ile30Val	missense_variant	2/10	2		ENSP00000427716.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000137 AC: 32 AN: 234176 Hom.: 0 AF XY: 0.000158 AC XY: 20 AN XY: 126312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000463

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.0000643 AC: 93 AN: 1445728 Hom.: 1 Cov.: 28 AF XY: 0.0000640 AC XY: 46 AN XY: 718748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000391

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.000234

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000295

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2021	The c.88A>G (p.I30V) alteration is located in exon 2 (coding exon 1) of the SPAG1 gene. This alteration results from a A to G substitution at nucleotide position 88, causing the isoleucine (I) at amino acid position 30 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2016	The p.I30V variant (also known as c.88A>G), located in coding exon 1 of the SPAG1 gene, results from an A to G substitution at nucleotide position 88. The isoleucine at codon 30 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 28 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 30 of the SPAG1 protein (p.Ile30Val). This variant is present in population databases (rs550123264, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SPAG1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;T;T;.
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.96	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.079	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.43	.;B;.;B
Vest4		0.31
MutPred		0.23		Loss of ubiquitination at K28 (P = 0.1278);Loss of ubiquitination at K28 (P = 0.1278);Loss of ubiquitination at K28 (P = 0.1278);Loss of ubiquitination at K28 (P = 0.1278);
MVP		0.46
MPC		0.23
ClinPred		0.058	T
GERP RS		4.5
Varity_R		0.065
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs550123264; hg19: chr8-101174596;