Genetic Variant NM_003114.5:c.133G>T (chr8-100162413-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003114.5(SPAG1):c.133G>T(p.Val45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SPAG1
NM_003114.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.33163428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG1	NM_003114.5 link	c.133G>T	p.Val45Leu	missense_variant	Exon 2 of 19	ENST00000388798.7	NP_003105.2	Q07617-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPAG1	ENST00000388798.7 link	c.133G>T	p.Val45Leu	missense_variant	Exon 2 of 19	1	NM_003114.5	ENSP00000373450.3	Q07617-1
SPAG1	ENST00000251809.4 link	c.133G>T	p.Val45Leu	missense_variant	Exon 2 of 19	5		ENSP00000251809.3	Q07617-1
SPAG1	ENST00000520508.5 link	c.133G>T	p.Val45Leu	missense_variant	Exon 2 of 10	5		ENSP00000428070.1	Q07617-2
SPAG1	ENST00000520643.5 link	c.133G>T	p.Val45Leu	missense_variant	Exon 2 of 10	2		ENSP00000427716.1	Q07617-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1425500

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708684

show subpopulations

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:

9.10e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

.;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

.;T;D;.

M_CAP

Benign

0.018

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.1

M;M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.017

D;D;D;D

Sift4G

Benign

0.093

T;T;T;T

Polyphen

0.99

.;D;.;D

Vest4

0.50

MutPred

0.30

Gain of catalytic residue at V45 (P = 0.0197);Gain of catalytic residue at V45 (P = 0.0197);Gain of catalytic residue at V45 (P = 0.0197);Gain of catalytic residue at V45 (P = 0.0197);

MVP

0.82

MPC

0.48

ClinPred

0.89

GERP RS

4.0

Varity_R

0.17

gMVP

0.60

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over