rs6511

chr8-100240452-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003114.5(SPAG1):c.2330T>C(p.Met777Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,613,048 control chromosomes in the GnomAD database, including 302,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (31128 hom., cov: 30)
  • Exomes 𝑓: 0.61 (271698 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.210

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8907637E-6).
• BP6: Variant 8-100240452-T-C is Benign according to our data. Variant chr8-100240452-T-C is described in ClinVar as [Benign]. Clinvar id is 262802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPAG1	NM_003114.5	c.2330T>C	p.Met777Thr	missense_variant	18/19	ENST00000388798.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPAG1	ENST00000388798.7	c.2330T>C	p.Met777Thr	missense_variant	18/19	1	NM_003114.5	P1
SPAG1	ENST00000251809.4	c.2330T>C	p.Met777Thr	missense_variant	18/19	5		P1
SPAG1	ENST00000519424.1	n.582T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96826 AN: 151754 Hom.: 31099 Cov.: 30

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.629

GnomAD3 exomes AF: 0.618 AC: 155095 AN: 250818 Hom.: 48541 AF XY: 0.611 AC XY: 82885 AN XY: 135608

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.504

Gnomad SAS exome AF: 0.560

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.615

Gnomad OTH exome AF: 0.614

GnomAD4 exome AF: 0.608 AC: 888959 AN: 1461176 Hom.: 271698 Cov.: 42 AF XY: 0.606 AC XY: 440419 AN XY: 726916

Gnomad4 AFR exome AF: 0.703

Gnomad4 AMR exome AF: 0.716

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.502

Gnomad4 SAS exome AF: 0.563

Gnomad4 FIN exome AF: 0.615

Gnomad4 NFE exome AF: 0.609

Gnomad4 OTH exome AF: 0.606

GnomAD4 genome AF: 0.638 AC: 96907 AN: 151872 Hom.: 31128 Cov.: 30 AF XY: 0.638 AC XY: 47319 AN XY: 74214

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.697

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.610

Gnomad4 OTH AF: 0.625

Alfa AF: 0.612 Hom.: 55379

Bravo AF: 0.647

TwinsUK AF: 0.604 AC: 2240

ALSPAC AF: 0.602 AC: 2320

ESP6500AA AF: 0.692 AC: 3051

ESP6500EA AF: 0.609 AC: 5241

ExAC AF: 0.617 AC: 74887

Asia WGS AF: 0.518 AC: 1805 AN: 3478

EpiCase AF: 0.611

EpiControl AF: 0.615

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 28 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.056
Dann	Benign	0.16
DEOGEN2	Benign	0.0077	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.089	T;.
MetaRNN	Benign	0.0000019	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.041
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.011
MPC		0.17
ClinPred		0.00030	T
GERP RS		-3.7
Varity_R		0.027
gMVP		0.19

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: rs6511; hg19: chr8-101252680; COSMIC: COSV52557997; COSMIC: COSV52557997;