chr8-100213407-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003114.5(SPAG1):c.1414A>G(p.Ile472Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,436,302 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 59 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.86

Publications

2 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005939007).

BP6

Variant 8-100213407-A-G is Benign according to our data. Variant chr8-100213407-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00361 (550/152188) while in subpopulation SAS AF = 0.027 (130/4822). AF 95% confidence interval is 0.0232. There are 3 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.1414A>G	p.Ile472Val	missense_variant	Exon 11 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.1414A>G	p.Ile472Val	missense_variant	Exon 11 of 19	1	NM_003114.5	ENSP00000373450.3	Q07617-1
SPAG1	ENST00000251809.4 link	c.1414A>G	p.Ile472Val	missense_variant	Exon 11 of 19	5		ENSP00000251809.3	Q07617-1
SPAG1	ENST00000523302.1 link	n.321A>G		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00361

AC:

549

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0267

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00823

AC:

422

AN:

51290

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00109

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00812

Gnomad EAS exome

AF:

0.000664

Gnomad FIN exome

AF:

0.000284

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00466

GnomAD4 exome

AF:

0.00567

AC:

7284

AN:

1284114

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

3924

AN XY:

631164

show subpopulations

African (AFR)

AF:

0.000704

AC:

AN:

25562

American (AMR)

AF:

0.00177

AC:

AN:

21520

Ashkenazi Jewish (ASJ)

AF:

0.00801

AC:

169

AN:

21096

East Asian (EAS)

AF:

0.0000708

AC:

AN:

28240

South Asian (SAS)

AF:

0.0245

AC:

1624

AN:

66374

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

38970

Middle Eastern (MID)

AF:

0.00303

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

0.00497

AC:

5103

AN:

1026164

Other (OTH)

AF:

0.00588

AC:

307

AN:

52234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

347

695

1042

1390

1737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<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:

0.00361

AC:

550

AN:

152188

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

266

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41560

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.0270

AC:

130

AN:

4822

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00478

AC:

325

AN:

67970

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00413

Hom.:

Bravo

AF:

0.00289

ExAC

AF:

0.00603

AC:

193

Asia WGS

AF:

0.00983

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 28

Benign:3

Mar 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 19, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary ciliary dyskinesia

Benign:1

Feb 09, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.044

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.68

T;.

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.99

L;L

PhyloP100

2.9

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.070

B;B

Vest4

0.25

MVP

0.68

MPC

0.21

ClinPred

0.012

GERP RS

3.7

Varity_R

0.17

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(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