8-100165842-C-A

Variant names:

• chr8-100165842-C-A
• NM_003114.5:c.169C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003114.5(SPAG1):​c.169C>A​(p.Leu57Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41110533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.169C>A	p.Leu57Ile	missense_variant	Exon 3 of 19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.169C>A	p.Leu57Ile	missense_variant	Exon 3 of 19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4	c.169C>A	p.Leu57Ile	missense_variant	Exon 3 of 19	5		ENSP00000251809.3
SPAG1	ENST00000520508.5	c.169C>A	p.Leu57Ile	missense_variant	Exon 3 of 10	5		ENSP00000428070.1
SPAG1	ENST00000520643.5	c.169C>A	p.Leu57Ile	missense_variant	Exon 3 of 10	2		ENSP00000427716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169C>A (p.L57I) alteration is located in exon 3 (coding exon 2) of the SPAG1 gene. This alteration results from a C to A substitution at nucleotide position 169, causing the leucine (L) at amino acid position 57 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.9	M;M;M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.57
MutPred		0.48		Loss of catalytic residue at L57 (P = 0.0251);Loss of catalytic residue at L57 (P = 0.0251);Loss of catalytic residue at L57 (P = 0.0251);Loss of catalytic residue at L57 (P = 0.0251);
MVP		0.94
MPC		0.67
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-101178070;