rs138503542

chr8-100191434-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003114.5(SPAG1):c.877C>T(p.Arg293Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,613,946 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011241555).
• BP6: Variant 8-100191434-C-T is Benign according to our data. Variant chr8-100191434-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00348 (530/152246) while in subpopulation AFR AF= 0.0119 (495/41534). AF 95% confidence interval is 0.011. There are 3 homozygotes in gnomad4. There are 244 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.877C>T	p.Arg293Trp	missense_variant	9/19	ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.877C>T	p.Arg293Trp	missense_variant	9/19	1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.877C>T	p.Arg293Trp	missense_variant	9/19	5		P1
SPAG1	ENST00000520508.5	c.877C>T	p.Arg293Trp	missense_variant	9/10	5
SPAG1	ENST00000520643.5	c.877C>T	p.Arg293Trp	missense_variant	9/10	2

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152128 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000951 AC: 239 AN: 251232 Hom.: 1 AF XY: 0.000729 AC XY: 99 AN XY: 135800

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461700 Hom.: 2 Cov.: 29 AF XY: 0.000340 AC XY: 247 AN XY: 727148

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152246 Hom.: 3 Cov.: 31 AF XY: 0.00328 AC XY: 244 AN XY: 74432

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000592 Hom.: 1

Bravo AF: 0.00400

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00115 AC: 140

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2017

This alteration is classified as 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.045
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.81	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D;N;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.98	.;D;.;D
Vest4		0.34
MVP		0.84
MPC		0.41
ClinPred		0.030	T
GERP RS		4.2
Varity_R		0.099
gMVP		0.22

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: rs138503542; hg19: chr8-101203662;