rs7074847

Positions:

• chr10-22386928-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012443.4(SPAG6):​c.647A>G​(p.Gln216Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0384 in 1,613,474 control chromosomes in the GnomAD database, including 10,837 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (5538 hom., cov: 32)
  • Exomes 𝑓: 0.026 (5299 hom.)
• Consequence: SPAG6 NM_012443.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18

Genes affected

SPAG6 (HGNC:11215): (sperm associated antigen 6) 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 antibodies from an infertile man. This protein localizes to the tail of permeabilized human sperm and contains eight contiguous armadillo repeats, a motif known to mediate protein-protein interactions. Studies in mice suggest that this protein is involved in sperm flagellar motility and maintenance of the structural integrity of mature sperm. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.201863E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPAG6	NM_012443.4	c.647A>G	p.Gln216Arg	missense_variant	5/11	ENST00000376624.8	NP_036575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPAG6	ENST00000376624.8	c.647A>G	p.Gln216Arg	missense_variant	5/11	1	NM_012443.4	ENSP00000365811	P1
	ENST00000422675.1	n.250+25507A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23700 AN: 152062 Hom.: 5502 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.0505 AC: 12679 AN: 250868 Hom.: 2317 AF XY: 0.0404 AC XY: 5472 AN XY: 135564

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.0456

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00895

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0407

GnomAD4 exome AF: 0.0261 AC: 38171 AN: 1461294 Hom.: 5299 Cov.: 32 AF XY: 0.0242 AC XY: 17615 AN XY: 726942

Gnomad4 AFR exome AF: 0.534

Gnomad4 AMR exome AF: 0.0457

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00914

Gnomad4 FIN exome AF: 0.00652

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0506

GnomAD4 genome AF: 0.156 AC: 23787 AN: 152180 Hom.: 5538 Cov.: 32 AF XY: 0.150 AC XY: 11190 AN XY: 74440

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.0767

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0459 Hom.: 2023

Bravo AF: 0.179

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.509 AC: 2243

ESP6500EA AF: 0.0160 AC: 138

ExAC AF: 0.0595 AC: 7224

Asia WGS AF: 0.0510 AC: 179 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.65
DEOGEN2	Benign	0.012	T;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;D;D
MetaRNN	Benign	0.00062	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	.;L;L;.
MutationTaster	Benign	6.6e-7	P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.65	.;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.43	.;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0010, 0.0020	.;B;B;.
Vest4		0.31
MPC		0.30
ClinPred		0.020	T
GERP RS		4.5
Varity_R		0.36
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs7074847; hg19: chr10-22675857;