rs148756457

Variant names:

• chr8-100240948-G-A
• rs148756457
• NM_003114.5:c.2707G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-100240948-G-A
• chr8-100240948-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003114.5(SPAG1):​c.2707G>A​(p.Asp903Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,612,994 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.569
• Publications: 3 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), G2P, PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01830548).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000198 (289/1461354) while in subpopulation MID AF = 0.0102 (59/5768). AF 95% confidence interval is 0.00814. There are 2 homozygotes in GnomAdExome4. There are 148 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.2707G>A	p.Asp903Asn	missense	Exon 19 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.2707G>A	p.Asp903Asn	missense	Exon 19 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.2707G>A	p.Asp903Asn	missense	Exon 19 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.2707G>A	p.Asp903Asn	missense	Exon 19 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.2707G>A	p.Asp903Asn	missense	Exon 19 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.2707G>A	p.Asp903Asn	missense	Exon 19 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151640 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 250974 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461354 Hom.: 2 Cov.: 36 AF XY: 0.000204 AC XY: 148 AN XY: 726954

African (AFR) AF: 0.000239 AC: 8 AN: 33468

American (AMR) AF: 0.0000895 AC: 4 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1111728

Other (OTH) AF: 0.000331 AC: 20 AN: 60362

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151640 Hom.: 0 Cov.: 31 AF XY: 0.000243 AC XY: 18 AN XY: 74028

African (AFR) AF: 0.00 AC: 0 AN: 41286

American (AMR) AF: 0.000263 AC: 4 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67934

Other (OTH) AF: 0.000960 AC: 2 AN: 2084

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Primary ciliary dyskinesia 28 (4)
-	1	-	not specified (1)
-	1	-	Primary ciliary dyskinesia (1)
-	1	-	SPAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.57
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.095
MVP		0.58
MPC		0.14
ClinPred		0.0069	T
GERP RS		2.1
Varity_R		0.039
gMVP		0.13
Mutation Taster		=98/2	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: rs148756457; hg19: chr8-101253176;