rs544372581

Positions:

• chr8-100213219-C-G
• chr8-100213219-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003114.5(SPAG1):​c.1226C>G​(p.Thr409Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,400,556 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.357

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036236048).
• BP6: Variant 8-100213219-C-G is Benign according to our data. Variant chr8-100213219-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410994.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00233 (351/150614) while in subpopulation AFR AF= 0.00774 (320/41348). AF 95% confidence interval is 0.00704. There are 2 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG1	NM_003114.5	c.1226C>G	p.Thr409Ser	missense_variant	11/19	ENST00000388798.7	NP_003105.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG1	ENST00000388798.7	c.1226C>G	p.Thr409Ser	missense_variant	11/19	1	NM_003114.5	ENSP00000373450	P1
SPAG1	ENST00000251809.4	c.1226C>G	p.Thr409Ser	missense_variant	11/19	5		ENSP00000251809	P1
SPAG1	ENST00000523302.1	n.133C>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 353 AN: 150508 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

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: 0.0000296

Gnomad OTH AF: 0.00338

GnomAD3 exomes AF: 0.000257 AC: 13 AN: 50630 Hom.: 0 AF XY: 0.000130 AC XY: 4 AN XY: 30772

Gnomad AFR exome AF: 0.00324

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000995

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 208 AN: 1249942 Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 89 AN XY: 616148

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.000749

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.000457

GnomAD4 genome AF: 0.00233 AC: 351 AN: 150614 Hom.: 2 Cov.: 33 AF XY: 0.00221 AC XY: 163 AN XY: 73614

Gnomad4 AFR AF: 0.00774

Gnomad4 AMR AF: 0.00146

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00334

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.00254

ExAC AF: 0.000222 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 28 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2022	The SPAG1 c.1226C>G, p.Thr409Ser variant (rs544372581), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 410994). This variant is found in the African/African-American population with an allele frequency of 0.66% (59/8966 alleles) in the Genome Aggregation Database. The threonine at codon 409 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.057). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SPAG1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.4
DANN	Benign	0.52
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.21	T;.
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.057
Sift	Benign	0.63	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0	B;B
Vest4		0.039
MutPred		0.21		Gain of glycosylation at T409 (P = 0.1346);Gain of glycosylation at T409 (P = 0.1346);
MVP		0.43
MPC		0.13
ClinPred		0.0037	T
GERP RS		-0.18
Varity_R		0.037
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs544372581; hg19: chr8-101225447;