Genetic Variant SPAG1:p.Ala427_Ala428dup (chr8-100213262-T-TGCGGCG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_003114.5(SPAG1):c.1280_1285dupCGGCGG(p.Ala427_Ala428dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,213,158 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SPAG1
NM_003114.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.672

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_003114.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.1280_1285dupCGGCGG	p.Ala427_Ala428dup	disruptive_inframe_insertion	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.1280_1285dupCGGCGG	p.Ala427_Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	1	NM_003114.5	ENSP00000373450.3	Q07617-1
SPAG1	ENST00000251809.4 link	c.1280_1285dupCGGCGG	p.Ala427_Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	5		ENSP00000251809.3	Q07617-1
SPAG1	ENST00000523302.1 link	n.187_192dupCGGCGG		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000402

AC:

AN:

149410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1063646

Hom.:

Cov.:

AF XY:

0.0000257

AC XY:

AN XY:

505802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21880

American (AMR)

AF:

0.00

AC:

AN:

7514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12930

East Asian (EAS)

AF:

0.00

AC:

AN:

24240

South Asian (SAS)

AF:

0.0000508

AC:

AN:

19676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2836

European-Non Finnish (NFE)

AF:

0.0000165

AC:

AN:

911790

Other (OTH)

AF:

0.0000239

AC:

AN:

41760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.0000401

AC:

AN:

149512

Hom.:

Cov.:

AF XY:

0.0000411

AC XY:

AN XY:

73018

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41198

American (AMR)

AF:

0.00

AC:

AN:

15056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

67032

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.67

Mutation Taster

=90/10

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over