chr8-100239389-A-T

Variant names:

• chr8-100239389-A-T
• rs148883126
• NM_003114.5:c.2265A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003114.5(SPAG1):​c.2265A>T​(p.Lys755Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,603,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: SPAG1 NM_003114.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.43
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026514143).
• BP6: Variant 8-100239389-A-T is Benign according to our data. Variant chr8-100239389-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410995.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00132 (201/152310) while in subpopulation NFE AF = 0.00248 (169/68018). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.2265A>T	p.Lys755Asn	missense	Exon 17 of 19	NP_003105.2
	SPAG1	NM_001374321.1		c.2265A>T	p.Lys755Asn	missense	Exon 17 of 19	NP_001361250.1	Q07617-1
	SPAG1	NM_172218.3		c.2265A>T	p.Lys755Asn	missense	Exon 17 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.2265A>T	p.Lys755Asn	missense	Exon 17 of 19	ENSP00000373450.3	Q07617-1
	SPAG1	ENST00000251809.4	TSL:5	c.2265A>T	p.Lys755Asn	missense	Exon 17 of 19	ENSP00000251809.3	Q07617-1
	SPAG1	ENST00000964470.1		c.2265A>T	p.Lys755Asn	missense	Exon 17 of 19	ENSP00000634529.1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00105 AC: 263 AN: 250746 AF XY: 0.00101

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00131 AC: 1902 AN: 1450790 Hom.: 2 Cov.: 27 AF XY: 0.00133 AC XY: 963 AN XY: 722542

African (AFR) AF: 0.000150 AC: 5 AN: 33248

American (AMR) AF: 0.000381 AC: 17 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85986

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00159 AC: 1747 AN: 1102126

Other (OTH) AF: 0.000716 AC: 43 AN: 60022

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74478

African (AFR) AF: 0.000289 AC: 12 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00248 AC: 169 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.000892

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00105 AC: 127

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia (2)
-	-	1	Primary ciliary dyskinesia 28 (1)
-	-	1	SPAG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.15
MutPred		0.26		Loss of ubiquitination at K755 (P = 0.0039)
MVP		0.74
MPC		0.62
ClinPred		0.060	T
GERP RS		4.9
Varity_R		0.20
gMVP		0.22
Mutation Taster		=73/27	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: rs148883126; hg19: chr8-101251617;