NM_003114.5:c.1057A>G

Variant names:

• chr8-100194229-A-G
• rs556774863
• NM_003114.5:c.1057A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_003114.5(SPAG1):​c.1057A>G​(p.Lys353Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,603,546 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.00
• 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), ClinGen, PanelApp Australia, G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005363822).
• BP6: Variant 8-100194229-A-G is Benign according to our data. Variant chr8-100194229-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000296 (43/145490) while in subpopulation EAS AF = 0.00566 (29/5126). AF 95% confidence interval is 0.00405. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	NM_003114.5	MANE Select	c.1057A>G	p.Lys353Glu	missense	Exon 10 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.1057A>G	p.Lys353Glu	missense	Exon 10 of 19	NP_001361250.1
	SPAG1	NM_172218.3		c.1057A>G	p.Lys353Glu	missense	Exon 10 of 19	NP_757367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.1057A>G	p.Lys353Glu	missense	Exon 10 of 19	ENSP00000373450.3
	SPAG1	ENST00000251809.4	TSL:5	c.1057A>G	p.Lys353Glu	missense	Exon 10 of 19	ENSP00000251809.3
	SPAG1	ENST00000520508.5	TSL:5	c.1057A>G	p.Lys353Glu	missense	Exon 10 of 10	ENSP00000428070.1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 44 AN: 145362 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00584

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000508

GnomAD2 exomes AF: 0.000457 AC: 108 AN: 236510 AF XY: 0.000430

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000621

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1458056 Hom.: 1 Cov.: 30 AF XY: 0.0000868 AC XY: 63 AN XY: 725504

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.0000224 AC: 1 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00275 AC: 109 AN: 39598

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108900

Other (OTH) AF: 0.000432 AC: 26 AN: 60236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000296 AC: 43 AN: 145490 Hom.: 0 Cov.: 33 AF XY: 0.000324 AC XY: 23 AN XY: 70926

African (AFR) AF: 0.000268 AC: 11 AN: 40976

American (AMR) AF: 0.0000693 AC: 1 AN: 14426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3258

East Asian (EAS) AF: 0.00566 AC: 29 AN: 5126

South Asian (SAS) AF: 0.000223 AC: 1 AN: 4476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64436

Other (OTH) AF: 0.000503 AC: 1 AN: 1990

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.000332

ExAC AF: 0.000347 AC: 41

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	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	0.077
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.9
DANN	Benign	0.26
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.023
Sift	Benign	0.16	T
Sift4G	Benign	0.082	T
Polyphen		0.16	B
Vest4		0.11
MVP		0.66
MPC		0.21
ClinPred		0.0020	T
GERP RS		3.0
Varity_R		0.080
gMVP		0.21
Mutation Taster		=99/1	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: rs556774863; hg19: chr8-101206457;