rs779765255

Positions:

• chr8-100191447-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000388798.7(SPAG1):​c.890A>G​(p.Glu297Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPAG1 ENST00000388798.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.890A>G	p.Glu297Gly	missense_variant	9/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.890A>G	p.Glu297Gly	missense_variant	9/19	1	NM_003114.5	ENSP00000373450	P1
SPAG1	ENST00000251809.4	c.890A>G	p.Glu297Gly	missense_variant	9/19	5		ENSP00000251809	P1
SPAG1	ENST00000520508.5	c.890A>G	p.Glu297Gly	missense_variant	9/10	5		ENSP00000428070
SPAG1	ENST00000520643.5	c.890A>G	p.Glu297Gly	missense_variant	9/10	2		ENSP00000427716

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251238 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135800

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461716 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 28 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces glutamic acid with glycine at codon 297 of the SPAG1 protein (p.Glu297Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs779765255, ExAC 0.003%). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.12
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.51	.;T;T;.
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.6	L;L;L;L
MutationTaster	Benign	0.86	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.11	T;D;T;D
Sift4G	Benign	0.14	T;D;T;D
Polyphen		1.0	.;D;.;D
Vest4		0.36
MutPred		0.47		Loss of stability (P = 0.0486);Loss of stability (P = 0.0486);Loss of stability (P = 0.0486);Loss of stability (P = 0.0486);
MVP		0.88
MPC		0.64
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.20
gMVP		0.33

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: rs779765255; hg19: chr8-101203675;