rs886037653

Positions:

• chr8-100240660-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000388798.7(SPAG1):​c.2542del​(p.Asp848IlefsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAG1 ENST00000388798.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.83

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-100240660-AG-A is Pathogenic according to our data. Variant chr8-100240660-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 88684.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.2542del	p.Asp848IlefsTer10	frameshift_variant	18/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.2542del	p.Asp848IlefsTer10	frameshift_variant	18/19	1	NM_003114.5	ENSP00000373450	P1
SPAG1	ENST00000251809.4	c.2542del	p.Asp848IlefsTer10	frameshift_variant	18/19	5		ENSP00000251809	P1
SPAG1	ENST00000519409.1	n.106del		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 28 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SPAG1 are known to be pathogenic (PMID: 24055112). This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24055112). ClinVar contains an entry for this variant (Variation ID: 88684). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp848Ilefs*10) in the SPAG1 gene. It is expected to result in an absent or disrupted protein product. -

Autosomal dominant nocturnal frontal lobe epilepsy 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs886037653; hg19: chr8-101252888;