Variant 10-22389220-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012443.4(SPAG6):c.913T>A(p.Cys305Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000698 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

SPAG6
NM_012443.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10

Variant links:

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]

SPAG6 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025702834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG6	NM_012443.4 linkuse as main transcript	c.913T>A	p.Cys305Ser	missense_variant	7/11	ENST00000376624.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG6	ENST00000376624.8 linkuse as main transcript	c.913T>A	p.Cys305Ser	missense_variant	7/11	1	NM_012443.4	P1	O75602-1
	ENST00000422675.1 linkuse as main transcript	n.251-23629T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000367

AC:

AN:

251010

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000696

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000728

AC:

1064

AN:

1461202

Hom.:

Cov.:

AF XY:

0.000697

AC XY:

507

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000892

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000407

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000672

Hom.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000928

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.913T>A (p.C305S) alteration is located in exon 7 (coding exon 7) of the SPAG6 gene. This alteration results from a T to A substitution at nucleotide position 913, causing the cysteine (C) at amino acid position 305 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.0027

T;T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.0099

MetaRNN

Benign

0.026

T;T;T;T

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.43

REVEL

Benign

0.091

Sift4G

Benign

0.94

T;T;T;T

Polyphen

0.0, 0.0010

.;B;B;.

Vest4

0.23

MutPred

0.50

.;Gain of disorder (P = 0.0025);Gain of disorder (P = 0.0025);.;

MVP

0.69

MPC

0.29

ClinPred

0.051

GERP RS

5.7

Varity_R

0.35

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over