8-100213262-TGCGGCGGCG-TGCGGCGGCGGCG

Variant names:

• chr8-100213262-T-TGCG
• rs962670800
• NM_003114.5:c.1283_1285dupCGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_003114.5(SPAG1):​c.1283_1285dupCGG​(p.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 0.0000593 in 1,213,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: SPAG1 NM_003114.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.672
• 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), G2P, PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003114.5. Strenght limited to Supporting due to length of the change: 1aa.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	NM_003114.5	MANE Select	c.1283_1285dupCGG	p.Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.1283_1285dupCGG	p.Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.1283_1285dupCGG	p.Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	NP_757367.1	Q07617-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.1283_1285dupCGG	p.Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.1283_1285dupCGG	p.Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.1283_1285dupCGG	p.Ala428dup	disruptive_inframe_insertion	Exon 11 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.0000469 AC: 7 AN: 149410 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

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: 0.0000298

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000611 AC: 65 AN: 1063646 Hom.: 0 Cov.: 32 AF XY: 0.0000474 AC XY: 24 AN XY: 505802

African (AFR) AF: 0.0000457 AC: 1 AN: 21880

American (AMR) AF: 0.00 AC: 0 AN: 7514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12930

East Asian (EAS) AF: 0.0000825 AC: 2 AN: 24240

South Asian (SAS) AF: 0.00 AC: 0 AN: 19676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21020

Middle Eastern (MID) AF: 0.000353 AC: 1 AN: 2836

European-Non Finnish (NFE) AF: 0.0000647 AC: 59 AN: 911790

Other (OTH) AF: 0.0000479 AC: 2 AN: 41760

GnomAD4 genome AF: 0.0000468 AC: 7 AN: 149512 Hom.: 0 Cov.: 33 AF XY: 0.0000411 AC XY: 3 AN XY: 73018

African (AFR) AF: 0.0000485 AC: 2 AN: 41198

American (AMR) AF: 0.000199 AC: 3 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia 28 (2)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.67
Mutation Taster		=89/11	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs962670800; hg19: chr8-101225490;