rs2514681

Variant names:

• chr8-100213331-C-G
• rs2514681
• NM_003114.5:c.1338C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-100213331-C-G
• chr8-100213331-C-T
• chr8-100213331-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003114.5(SPAG1):​c.1338C>G​(p.Ala446Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,311,082 control chromosomes in the GnomAD database, including 85,679 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A446A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.33 (8831 hom., cov: 32)
  • Exomes 𝑓: 0.36 (76848 hom.)
• Consequence: SPAG1 NM_003114.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.181
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-100213331-C-G is Benign according to our data. Variant chr8-100213331-C-G is described in ClinVar as Benign. ClinVar VariationId is 262801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.181 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

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.1338C>G	p.Ala446Ala	synonymous	Exon 11 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.1338C>G	p.Ala446Ala	synonymous	Exon 11 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.1338C>G	p.Ala446Ala	synonymous	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.1338C>G	p.Ala446Ala	synonymous	Exon 11 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.1338C>G	p.Ala446Ala	synonymous	Exon 11 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.1338C>G	p.Ala446Ala	synonymous	Exon 11 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 49893 AN: 150894 Hom.: 8823 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.411 AC: 12927 AN: 31432 AF XY: 0.405

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.361 AC: 419212 AN: 1160076 Hom.: 76848 Cov.: 33 AF XY: 0.362 AC XY: 203150 AN XY: 561644

African (AFR) AF: 0.216 AC: 5117 AN: 23734

American (AMR) AF: 0.497 AC: 6145 AN: 12364

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 6115 AN: 17486

East Asian (EAS) AF: 0.493 AC: 13330 AN: 27042

South Asian (SAS) AF: 0.320 AC: 12163 AN: 38046

European-Finnish (FIN) AF: 0.340 AC: 10548 AN: 30988

Middle Eastern (MID) AF: 0.308 AC: 1024 AN: 3320

European-Non Finnish (NFE) AF: 0.362 AC: 348162 AN: 960720

Other (OTH) AF: 0.358 AC: 16608 AN: 46376

GnomAD4 genome AF: 0.331 AC: 49921 AN: 151006 Hom.: 8831 Cov.: 32 AF XY: 0.332 AC XY: 24536 AN XY: 73802

African (AFR) AF: 0.223 AC: 9211 AN: 41368

American (AMR) AF: 0.450 AC: 6846 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1198 AN: 3452

East Asian (EAS) AF: 0.510 AC: 2606 AN: 5114

South Asian (SAS) AF: 0.301 AC: 1451 AN: 4820

European-Finnish (FIN) AF: 0.334 AC: 3399 AN: 10180

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.357 AC: 24091 AN: 67574

Other (OTH) AF: 0.334 AC: 701 AN: 2096

Alfa AF: 0.182 Hom.: 370

Bravo AF: 0.337

Asia WGS AF: 0.389 AC: 1349 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia 28 (2)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.8
DANN	Benign	0.59
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs2514681; hg19: chr8-101225559; COSMIC: COSV52557673;