rs6511

Variant names:

• chr8-100240452-T-C
• rs6511
• NM_003114.5:c.2330T>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M777I) has been classified as Likely benign.

• 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:6
• Conservation: PhyloP100: -0.210
• Publications: 45 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: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.2330T>C	p.Met777Thr	missense	Exon 18 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.2330T>C	p.Met777Thr	missense	Exon 18 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.2330T>C	p.Met777Thr	missense	Exon 18 of 19	NP_757367.1	Q07617-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAG1	ENST00000388798.7	TSL:1 MANE Select	c.2330T>C	p.Met777Thr	missense	Exon 18 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.2330T>C	p.Met777Thr	missense	Exon 18 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.2330T>C	p.Met777Thr	missense	Exon 18 of 19	ENSP00000634529.1

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

GnomAD2 exomes AF: 0.618 AC: 155095 AN: 250818 AF XY: 0.611

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 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

African (AFR) AF: 0.703 AC: 23519 AN: 33452

American (AMR) AF: 0.716 AC: 31964 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 15012 AN: 26098

East Asian (EAS) AF: 0.502 AC: 19923 AN: 39686

South Asian (SAS) AF: 0.563 AC: 48543 AN: 86184

European-Finnish (FIN) AF: 0.615 AC: 32860 AN: 53402

Middle Eastern (MID) AF: 0.623 AC: 3591 AN: 5766

European-Non Finnish (NFE) AF: 0.609 AC: 676988 AN: 1111570

Other (OTH) AF: 0.606 AC: 36559 AN: 60370

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

African (AFR) AF: 0.701 AC: 29009 AN: 41388

American (AMR) AF: 0.697 AC: 10647 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2019 AN: 3472

East Asian (EAS) AF: 0.519 AC: 2677 AN: 5158

South Asian (SAS) AF: 0.542 AC: 2605 AN: 4808

European-Finnish (FIN) AF: 0.610 AC: 6427 AN: 10532

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41415 AN: 67928

Other (OTH) AF: 0.625 AC: 1314 AN: 2102

Alfa AF: 0.617 Hom.: 108444

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia 28 (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.21
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.17
ClinPred		0.00030	T
GERP RS		-3.7
Varity_R		0.027
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

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