rs1229952265

Variant names:

• chr8-100213149-C-T
• rs1229952265
• NM_003114.5:c.1156C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003114.5(SPAG1):​c.1156C>T​(p.Gln386*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000301 in 1,330,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SPAG1 NM_003114.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.18
• Publications: 0 publications found

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

ENSG00000302563 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 8-100213149-C-T is Pathogenic according to our data. Variant chr8-100213149-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 474648.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003114.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	NM_003114.5	MANE Select	c.1156C>T	p.Gln386*	stop_gained	Exon 11 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.1156C>T	p.Gln386*	stop_gained	Exon 11 of 19	NP_001361250.1
	SPAG1	NM_172218.3		c.1156C>T	p.Gln386*	stop_gained	Exon 11 of 19	NP_757367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.1156C>T	p.Gln386*	stop_gained	Exon 11 of 19	ENSP00000373450.3
	SPAG1	ENST00000251809.4	TSL:5	c.1156C>T	p.Gln386*	stop_gained	Exon 11 of 19	ENSP00000251809.3
	SPAG1	ENST00000523302.1	TSL:3	n.63C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000123 AC: 1 AN: 81426 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000346

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000301 AC: 4 AN: 1330238 Hom.: 0 Cov.: 32 AF XY: 0.00000457 AC XY: 3 AN XY: 656212

African (AFR) AF: 0.00 AC: 0 AN: 26966

American (AMR) AF: 0.00 AC: 0 AN: 27980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23566

East Asian (EAS) AF: 0.00 AC: 0 AN: 28384

South Asian (SAS) AF: 0.00 AC: 0 AN: 74580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5408

European-Non Finnish (NFE) AF: 0.00000379 AC: 4 AN: 1055168

Other (OTH) AF: 0.00 AC: 0 AN: 55308

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 28 Pathogenic:1

Mar 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SPAG1 are known to be pathogenic (PMID: 24055112). This sequence change creates a premature translational stop signal at codon 386 (p.Gln386*) of the SPAG1 gene. It is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		2.2
Vest4		0.094
GERP RS		2.4
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1229952265; hg19: chr8-101225377;