rs143621160

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003114.5(SPAG1):c.1954A>T(p.Ile652Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,599,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.930

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 28
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.1954A>T	p.Ile652Phe	missense_variant	Exon 15 of 19	ENST00000388798.7	NP_003105.2	Q07617-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPAG1	ENST00000388798.7 link	c.1954A>T	p.Ile652Phe	missense_variant	Exon 15 of 19	1	NM_003114.5	ENSP00000373450.3	Q07617-1
SPAG1	ENST00000251809.4 link	c.1954A>T	p.Ile652Phe	missense_variant	Exon 15 of 19	5		ENSP00000251809.3	Q07617-1
SPAG1	ENST00000523302.1 link	n.608A>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000105

AC:

AN:

248616

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000884

AC:

128

AN:

1447650

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

720562

show subpopulations

African (AFR)

AF:

0.0000603

AC:

AN:

33182

American (AMR)

AF:

0.000181

AC:

AN:

44092

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

39454

South Asian (SAS)

AF:

0.00

AC:

AN:

84254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52836

Middle Eastern (MID)

AF:

0.000353

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0000889

AC:

AN:

1102686

Other (OTH)

AF:

0.000285

AC:

AN:

59704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41472

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68048

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 28

Uncertain:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 652 of the SPAG1 protein (p.Ile652Phe). This variant is present in population databases (rs143621160, gnomAD 0.02%). 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: 410998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPAG1 protein function with a negative predictive value of 80%. 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. -

Primary ciliary dyskinesia

Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1954A>T (p.I652F) alteration is located in exon 15 (coding exon 14) of the SPAG1 gene. This alteration results from a A to T substitution at nucleotide position 1954, causing the isoleucine (I) at amino acid position 652 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.61

T;.

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.5

L;L

PhyloP100

0.93

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.16

Sift

Uncertain

0.025

D;D

Sift4G

Benign

0.13

T;T

Polyphen

1.0

D;D

Vest4

0.54

MVP

0.84

MPC

0.45

ClinPred

0.32

GERP RS

4.3

Varity_R

0.26

gMVP

0.37

Mutation Taster

=47/53

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over