8-100240948-G-C

Variant names:

• chr8-100240948-G-C
• NM_003114.5:c.2707G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003114.5(SPAG1):​c.2707G>C​(p.Asp903His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.569

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044403493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.2707G>C	p.Asp903His	missense_variant	Exon 19 of 19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.2707G>C	p.Asp903His	missense_variant	Exon 19 of 19	1	NM_003114.5	ENSP00000373450.3
SPAG1	ENST00000251809.4	c.2707G>C	p.Asp903His	missense_variant	Exon 19 of 19	5		ENSP00000251809.3
SPAG1	ENST00000519409.1	n.213+177G>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461354 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.10
Sift	Benign	0.34	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.011	B;B
Vest4		0.10
MutPred		0.54		Loss of stability (P = 0.0383);Loss of stability (P = 0.0383);
MVP		0.59
MPC		0.18
ClinPred		0.068	T
GERP RS		2.1
Varity_R		0.057
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-101253176;