chr8-100187131-C-T

Variant names:

• chr8-100187131-C-T
• rs755306741
• NM_003114.5:c.713C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_003114.5(SPAG1):​c.713C>T​(p.Ala238Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000771 in 1,609,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 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. A238A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.25
• 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

ENSG00000302563 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 8-100187131-C-T is Benign according to our data. Variant chr8-100187131-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410996.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000224 (34/152032) while in subpopulation AMR AF = 0.00197 (30/15250). AF 95% confidence interval is 0.00142. There are 0 homozygotes in GnomAd4. There are 24 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.713C>T	p.Ala238Val	missense	Exon 8 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.713C>T	p.Ala238Val	missense	Exon 8 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.713C>T	p.Ala238Val	missense	Exon 8 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.713C>T	p.Ala238Val	missense	Exon 8 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.713C>T	p.Ala238Val	missense	Exon 8 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.713C>T	p.Ala238Val	missense	Exon 8 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

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: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000723 AC: 18 AN: 248798 AF XY: 0.0000595

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.0000618 AC: 90 AN: 1457030 Hom.: 0 Cov.: 30 AF XY: 0.0000552 AC XY: 40 AN XY: 724886

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.000384 AC: 17 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00 AC: 0 AN: 85412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.0000622 AC: 69 AN: 1109494

Other (OTH) AF: 0.0000499 AC: 3 AN: 60118

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.00197 AC: 30 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.69
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.044
Sift	Benign	0.66	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.23
MutPred		0.45		Gain of catalytic residue at A238 (P = 0.0229)
MVP		0.54
MPC		0.15
ClinPred		0.013	T
GERP RS		0.47
Varity_R		0.021
gMVP		0.099
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755306741; hg19: chr8-101199359; COSMIC: COSV105093568; COSMIC: COSV105093568;