rs138503542

Variant names:

• chr8-100191434-C-T
• rs138503542
• NM_003114.5:c.877C>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.877C>T​(p.Arg293Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,613,946 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.05
• Publications: 5 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=0.011241555).
• BP6: Variant 8-100191434-C-T is Benign according to our data. Variant chr8-100191434-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00348 (530/152246) while in subpopulation AFR AF = 0.0119 (495/41534). AF 95% confidence interval is 0.011. There are 3 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.877C>T	p.Arg293Trp	missense	Exon 9 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.877C>T	p.Arg293Trp	missense	Exon 9 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.877C>T	p.Arg293Trp	missense	Exon 9 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.877C>T	p.Arg293Trp	missense	Exon 9 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.877C>T	p.Arg293Trp	missense	Exon 9 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.877C>T	p.Arg293Trp	missense	Exon 9 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152128 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000951 AC: 239 AN: 251232 AF XY: 0.000729

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461700 Hom.: 2 Cov.: 29 AF XY: 0.000340 AC XY: 247 AN XY: 727148

African (AFR) AF: 0.0121 AC: 404 AN: 33472

American (AMR) AF: 0.000783 AC: 35 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111910

Other (OTH) AF: 0.000961 AC: 58 AN: 60382

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152246 Hom.: 3 Cov.: 31 AF XY: 0.00328 AC XY: 244 AN XY: 74432

African (AFR) AF: 0.0119 AC: 495 AN: 41534

American (AMR) AF: 0.00124 AC: 19 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.00400

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00115 AC: 140

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.0
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.22
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.34
MVP		0.84
MPC		0.41
ClinPred		0.030	T
GERP RS		4.2
Varity_R		0.099
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: rs138503542; hg19: chr8-101203662;