rs369126472

chr8-100191399-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003114.5(SPAG1):c.842G>A(p.Arg281His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,611,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R281C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.84

Variant links:

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]

SPAG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5 linkuse as main transcript	c.842G>A	p.Arg281His	missense_variant	9/19	ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7 linkuse as main transcript	c.842G>A	p.Arg281His	missense_variant	9/19	1	NM_003114.5	P1	Q07617-1
SPAG1	ENST00000251809.4 linkuse as main transcript	c.842G>A	p.Arg281His	missense_variant	9/19	5		P1	Q07617-1
SPAG1	ENST00000520508.5 linkuse as main transcript	c.842G>A	p.Arg281His	missense_variant	9/10	5			Q07617-2
SPAG1	ENST00000520643.5 linkuse as main transcript	c.842G>A	p.Arg281His	missense_variant	9/10	2			Q07617-2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250284

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000292

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1459320

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

726036

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000699

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000171

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000409

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:

0.000118

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 28

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 281 of the SPAG1 protein (p.Arg281His). This variant is present in population databases (rs369126472, gnomAD 0.03%). 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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 576795). This variant has not been reported in the literature in individuals affected with SPAG1-related conditions. -

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.842G>A (p.R281H) alteration is located in exon 9 (coding exon 8) of the SPAG1 gene. This alteration results from a G to A substitution at nucleotide position 842, causing the arginine (R) at amino acid position 281 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Pathogenic

0.19

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.7

H;H;H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.029

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.91

MVP

0.93

MPC

0.71

ClinPred

0.98

GERP RS

5.1

Varity_R

0.60

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over