rs142031266

Variant names:

• chr8-100240955-C-T
• rs142031266
• NM_003114.5:c.2714C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003114.5(SPAG1):​c.2714C>T​(p.Ser905Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,609,926 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S905S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.82
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041397214).
• BP6: Variant 8-100240955-C-T is Benign according to our data. Variant chr8-100240955-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242015.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00167 (248/148834) while in subpopulation AFR AF = 0.00566 (228/40314). AF 95% confidence interval is 0.00505. There are 2 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2714C>T	p.Ser905Leu	missense	Exon 19 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.2714C>T	p.Ser905Leu	missense	Exon 19 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.2714C>T	p.Ser905Leu	missense	Exon 19 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.2714C>T	p.Ser905Leu	missense	Exon 19 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.2714C>T	p.Ser905Leu	missense	Exon 19 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.2714C>T	p.Ser905Leu	missense	Exon 19 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 244 AN: 148746 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000941

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000633

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000491

GnomAD2 exomes AF: 0.000474 AC: 119 AN: 251106 AF XY: 0.000317

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1461092 Hom.: 2 Cov.: 36 AF XY: 0.000180 AC XY: 131 AN XY: 726854

African (AFR) AF: 0.00628 AC: 210 AN: 33446

American (AMR) AF: 0.000425 AC: 19 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111494

Other (OTH) AF: 0.000464 AC: 28 AN: 60360

GnomAD4 genome AF: 0.00167 AC: 248 AN: 148834 Hom.: 2 Cov.: 31 AF XY: 0.00171 AC XY: 124 AN XY: 72354

African (AFR) AF: 0.00566 AC: 228 AN: 40314

American (AMR) AF: 0.000940 AC: 14 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.000635 AC: 3 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67518

Other (OTH) AF: 0.000486 AC: 1 AN: 2056

Alfa AF: 0.00160 Hom.: 1

Bravo AF: 0.00195

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia 28 (2)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.087
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.080	B
Vest4		0.086
MVP		0.64
MPC		0.14
ClinPred		0.019	T
GERP RS		1.7
Varity_R		0.094
gMVP		0.22
Mutation Taster		=97/3	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: rs142031266; hg19: chr8-101253183;