rs761617724

Variant names:

• chr8-100213300-C-A
• rs761617724
• NM_003114.5:c.1307C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-100213300-C-A
• chr8-100213300-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003114.5(SPAG1):​c.1307C>A​(p.Pro436Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,081,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P436L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.227
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07131618).

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.1307C>A	p.Pro436Gln	missense	Exon 11 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.1307C>A	p.Pro436Gln	missense	Exon 11 of 19	NP_001361250.1
	SPAG1	NM_172218.3		c.1307C>A	p.Pro436Gln	missense	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.1307C>A	p.Pro436Gln	missense	Exon 11 of 19	ENSP00000373450.3
	SPAG1	ENST00000251809.4	TSL:5	c.1307C>A	p.Pro436Gln	missense	Exon 11 of 19	ENSP00000251809.3
	SPAG1	ENST00000523302.1	TSL:3	n.214C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000462 AC: 5 AN: 1081660 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 515094

African (AFR) AF: 0.00 AC: 0 AN: 22364

American (AMR) AF: 0.00 AC: 0 AN: 8060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13802

East Asian (EAS) AF: 0.00 AC: 0 AN: 25736

South Asian (SAS) AF: 0.00 AC: 0 AN: 20268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.00000542 AC: 5 AN: 921872

Other (OTH) AF: 0.00 AC: 0 AN: 42876

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.5
DANN	Benign	0.91
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.23
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.069
Sift	Benign	0.48	T
Sift4G	Benign	0.31	T
Polyphen		0.21	B
Vest4		0.13
MutPred		0.18		Gain of MoRF binding (P = 0.0807)
MVP		0.44
MPC		0.14
ClinPred		0.058	T
GERP RS		-0.89
Varity_R		0.027
gMVP		0.24
Mutation Taster		=99/1	polymorphism

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: rs761617724; hg19: chr8-101225528;