rs556774863

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_003114.5(SPAG1):ā€‹c.1057A>Gā€‹(p.Lys353Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,603,546 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00030 ( 0 hom., cov: 33)
Exomes š‘“: 0.00010 ( 1 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

1
18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.005363822).
BP6
Variant 8-100194229-A-G is Benign according to our data. Variant chr8-100194229-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 474646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000296 (43/145490) while in subpopulation EAS AF= 0.00566 (29/5126). AF 95% confidence interval is 0.00405. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPAG1NM_003114.5 linkc.1057A>G p.Lys353Glu missense_variant 10/19 ENST00000388798.7 NP_003105.2 Q07617-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPAG1ENST00000388798.7 linkc.1057A>G p.Lys353Glu missense_variant 10/191 NM_003114.5 ENSP00000373450.3 Q07617-1
SPAG1ENST00000251809.4 linkc.1057A>G p.Lys353Glu missense_variant 10/195 ENSP00000251809.3 Q07617-1
SPAG1ENST00000520508.5 linkc.1057A>G p.Lys353Glu missense_variant 10/105 ENSP00000428070.1 Q07617-2
SPAG1ENST00000520643.5 linkc.1057A>G p.Lys353Glu missense_variant 10/102 ENSP00000427716.1 Q07617-2

Frequencies

GnomAD3 genomes
AF:
0.000303
AC:
44
AN:
145362
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000269
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000694
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00584
Gnomad SAS
AF:
0.000223
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000508
GnomAD3 exomes
AF:
0.000457
AC:
108
AN:
236510
Hom.:
1
AF XY:
0.000430
AC XY:
55
AN XY:
127902
show subpopulations
Gnomad AFR exome
AF:
0.000187
Gnomad AMR exome
AF:
0.0000621
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00549
Gnomad SAS exome
AF:
0.0000712
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000176
GnomAD4 exome
AF:
0.000104
AC:
152
AN:
1458056
Hom.:
1
Cov.:
30
AF XY:
0.0000868
AC XY:
63
AN XY:
725504
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00275
Gnomad4 SAS exome
AF:
0.000105
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000541
Gnomad4 OTH exome
AF:
0.000432
GnomAD4 genome
AF:
0.000296
AC:
43
AN:
145490
Hom.:
0
Cov.:
33
AF XY:
0.000324
AC XY:
23
AN XY:
70926
show subpopulations
Gnomad4 AFR
AF:
0.000268
Gnomad4 AMR
AF:
0.0000693
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00566
Gnomad4 SAS
AF:
0.000223
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000503
Alfa
AF:
0.000395
Hom.:
0
Bravo
AF:
0.000332
ExAC
AF:
0.000347
AC:
41

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 28 Benign:2
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 03, 2022- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2023- -
Primary ciliary dyskinesia Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 22, 2018This 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. -
SPAG1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 18, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
6.9
DANN
Benign
0.26
DEOGEN2
Benign
0.011
.;T;.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.20
.;T;T;.
M_CAP
Benign
0.0058
T
MetaRNN
Benign
0.0054
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L;L;L;L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.95
N;N;N;N
REVEL
Benign
0.023
Sift
Benign
0.16
T;T;T;T
Sift4G
Benign
0.082
T;T;T;T
Polyphen
0.16
.;B;.;B
Vest4
0.11
MVP
0.66
MPC
0.21
ClinPred
0.0020
T
GERP RS
3.0
Varity_R
0.080
gMVP
0.21

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.

Other links and lift over

dbSNP: rs556774863; hg19: chr8-101206457; API