rs752257877

Variant names:

• chr8-100213096-C-T
• rs752257877
• NM_003114.5:c.1103C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003114.5(SPAG1):​c.1103C>T​(p.Ala368Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,470,828 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.343
• 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), G2P, PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043658614).
• BP6: Variant 8-100213096-C-T is Benign according to our data. Variant chr8-100213096-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152124) while in subpopulation NFE AF = 0.00321 (218/67986). AF 95% confidence interval is 0.00286. There are 3 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	NM_003114.5	MANE Select	c.1103C>T	p.Ala368Val	missense	Exon 11 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.1103C>T	p.Ala368Val	missense	Exon 11 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.1103C>T	p.Ala368Val	missense	Exon 11 of 19	NP_757367.1	Q07617-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.1103C>T	p.Ala368Val	missense	Exon 11 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.1103C>T	p.Ala368Val	missense	Exon 11 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.1103C>T	p.Ala368Val	missense	Exon 11 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152016 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00238 AC: 178 AN: 74852 AF XY: 0.00210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000702

Gnomad ASJ exome AF: 0.000155

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00157 AC: 2069 AN: 1318704 Hom.: 10 Cov.: 32 AF XY: 0.00159 AC XY: 1035 AN XY: 650818

African (AFR) AF: 0.000152 AC: 4 AN: 26398

American (AMR) AF: 0.0000781 AC: 2 AN: 25598

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 8 AN: 23206

East Asian (EAS) AF: 0.0000357 AC: 1 AN: 28012

South Asian (SAS) AF: 0.00 AC: 0 AN: 73772

European-Finnish (FIN) AF: 0.0177 AC: 574 AN: 32370

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5432

European-Non Finnish (NFE) AF: 0.00134 AC: 1410 AN: 1049366

Other (OTH) AF: 0.00126 AC: 69 AN: 54550

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152124 Hom.: 3 Cov.: 33 AF XY: 0.00342 AC XY: 254 AN XY: 74372

African (AFR) AF: 0.000145 AC: 6 AN: 41486

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00321 AC: 218 AN: 67986

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00588 Hom.: 2

Bravo AF: 0.000960

ExAC AF: 0.000449 AC: 16

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Primary ciliary dyskinesia 28 (1)
-	-	1	SPAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.34
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.025
Sift	Benign	0.13	T
Sift4G	Benign	0.47	T
Polyphen		0.0040	B
Vest4		0.039
MVP		0.52
MPC		0.15
ClinPred		0.040	T
GERP RS		-0.59
Varity_R		0.053
gMVP		0.22
Mutation Taster		=98/2	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: rs752257877; hg19: chr8-101225324;