chr8-100184628-G-C

Variant names:

• chr8-100184628-G-C
• rs35305781
• NM_003114.5:c.596G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_003114.5(SPAG1):​c.596G>C​(p.Gly199Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00129 in 1,546,698 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: SPAG1 NM_003114.5 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.83
• 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), ClinGen, PanelApp Australia, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 8-100184628-G-C is Benign according to our data. Variant chr8-100184628-G-C is described in ClinVar as Benign. ClinVar VariationId is 416529.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 = 0.00679 (1033/152092) while in subpopulation AFR AF = 0.0233 (967/41480). AF 95% confidence interval is 0.0221. There are 13 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.596G>C	p.Gly199Ala	missense splice_region	Exon 7 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.596G>C	p.Gly199Ala	missense splice_region	Exon 7 of 19	NP_001361250.1
	SPAG1	NM_172218.3		c.596G>C	p.Gly199Ala	missense splice_region	Exon 7 of 19	NP_757367.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.596G>C	p.Gly199Ala	missense splice_region	Exon 7 of 19	ENSP00000373450.3
	SPAG1	ENST00000251809.4	TSL:5	c.596G>C	p.Gly199Ala	missense splice_region	Exon 7 of 19	ENSP00000251809.3
	SPAG1	ENST00000964470.1		c.596G>C	p.Gly199Ala	missense splice_region	Exon 7 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1034 AN: 151974 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00179 AC: 373 AN: 208892 AF XY: 0.00124

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.000406

GnomAD4 exome AF: 0.000686 AC: 957 AN: 1394606 Hom.: 11 Cov.: 26 AF XY: 0.000623 AC XY: 433 AN XY: 695146

African (AFR) AF: 0.0238 AC: 700 AN: 29468

American (AMR) AF: 0.00188 AC: 62 AN: 32904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24996

East Asian (EAS) AF: 0.00 AC: 0 AN: 36400

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52802

Middle Eastern (MID) AF: 0.00426 AC: 24 AN: 5636

European-Non Finnish (NFE) AF: 0.0000901 AC: 97 AN: 1077106

Other (OTH) AF: 0.00125 AC: 72 AN: 57790

GnomAD4 genome AF: 0.00679 AC: 1033 AN: 152092 Hom.: 13 Cov.: 32 AF XY: 0.00668 AC XY: 497 AN XY: 74368

African (AFR) AF: 0.0233 AC: 967 AN: 41480

American (AMR) AF: 0.00282 AC: 43 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67980

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.000522 Hom.: 0

Bravo AF: 0.00795

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00225 AC: 273

Asia WGS AF: 0.000868 AC: 3 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.23
Sift	Benign	0.47	T
Sift4G	Benign	0.46	T
Polyphen		1.0	D
Vest4		0.35
MVP		0.88
MPC		0.62
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.35
gMVP		0.37
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.090		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: rs35305781; hg19: chr8-101196856;