rs141605537

Variant names:

• chr8-100177928-T-C
• rs141605537
• NM_003114.5:c.413T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003114.5(SPAG1):​c.413T>C​(p.Leu138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,612,570 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L138F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.32
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005811155).
• BP6: Variant 8-100177928-T-C is Benign according to our data. Variant chr8-100177928-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541535.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000847 (129/152336) while in subpopulation AFR AF = 0.00279 (116/41576). AF 95% confidence interval is 0.00238. There are 1 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.413T>C	p.Leu138Pro	missense	Exon 4 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.413T>C	p.Leu138Pro	missense	Exon 4 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.413T>C	p.Leu138Pro	missense	Exon 4 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.413T>C	p.Leu138Pro	missense	Exon 4 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.413T>C	p.Leu138Pro	missense	Exon 4 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.413T>C	p.Leu138Pro	missense	Exon 4 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000274 AC: 68 AN: 248560 AF XY: 0.000171

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1460234 Hom.: 0 Cov.: 28 AF XY: 0.000105 AC XY: 76 AN XY: 726480

African (AFR) AF: 0.00281 AC: 94 AN: 33414

American (AMR) AF: 0.000179 AC: 8 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

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

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1110894

Other (OTH) AF: 0.000265 AC: 16 AN: 60304

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.000805 AC XY: 60 AN XY: 74494

African (AFR) AF: 0.00279 AC: 116 AN: 41576

American (AMR) AF: 0.000458 AC: 7 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000489 Hom.: 2

Bravo AF: 0.00103

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

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)
-	-	1	SPAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.028
Sift	Benign	0.22	T
Sift4G	Benign	0.21	T
Polyphen		0.0050	B
Vest4		0.14
MVP		0.36
MPC		0.25
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.18
gMVP		0.32
Mutation Taster		=82/18	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: rs141605537; hg19: chr8-101190156;