rs199515118

chr8-100191459-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003114.5(SPAG1):c.902A>G(p.Lys301Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.631

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035443276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.902A>G	p.Lys301Arg	missense_variant	9/19	ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.902A>G	p.Lys301Arg	missense_variant	9/19	1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.902A>G	p.Lys301Arg	missense_variant	9/19	5		P1
SPAG1	ENST00000520508.5	c.902A>G	p.Lys301Arg	missense_variant	9/10	5
SPAG1	ENST00000520643.5	c.902A>G	p.Lys301Arg	missense_variant	9/10	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000478 AC: 12 AN: 251198 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135780

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000289

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: 0.0000123 AC: 18 AN: 1461474 Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5 AN XY: 727036

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152312 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74480

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.0000653

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

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

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

Invitae

Jun 23, 2022

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 301 of the SPAG1 protein (p.Lys301Arg). This variant is present in population databases (rs199515118, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with SPAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 579799). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M;M;M;M
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.26	.;B;.;B
Vest4		0.14
MVP		0.81
MPC		0.13
ClinPred		0.62	D
GERP RS		5.1
Varity_R		0.10
gMVP		0.19

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: rs199515118; hg19: chr8-101203687;