2-213310151-A-T

Variant names:

• chr2-213310151-A-T
• rs2063122901
• NM_024532.5:c.372A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024532.5(SPAG16):​c.372A>T​(p.Arg124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPAG16 NM_024532.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.922

Genes affected

SPAG16 (HGNC:23225): (sperm associated antigen 16) Cilia and flagella are comprised of a microtubular backbone, the axoneme, which is organized by the basal body and surrounded by plasma membrane. SPAG16 encodes 2 major proteins that associate with the axoneme of sperm tail and the nucleus of postmeiotic germ cells, respectively (Zhang et al., 2007 [PubMed 17699735]).[supplied by OMIM, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPAG16	NM_024532.5	c.372A>T	p.Arg124Ser	missense_variant	Exon 4 of 16	ENST00000331683.10	NP_078808.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPAG16	ENST00000331683.10	c.372A>T	p.Arg124Ser	missense_variant	Exon 4 of 16	1	NM_024532.5	ENSP00000332592.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457744 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725330

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.372A>T (p.R124S) alteration is located in exon 4 (coding exon 4) of the SPAG16 gene. This alteration results from a A to T substitution at nucleotide position 372, causing the arginine (R) at amino acid position 124 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	.;L;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Benign	0.064	T;T;T;T;T
Sift4G	Benign	0.085	T;T;D;T;T
Polyphen		0.99	.;D;D;.;.
Vest4		0.83, 0.88, 0.90, 0.91
MutPred		0.72		Gain of ubiquitination at K119 (P = 0.0557);Gain of ubiquitination at K119 (P = 0.0557);Gain of ubiquitination at K119 (P = 0.0557);.;Gain of ubiquitination at K119 (P = 0.0557);
MVP		0.79
MPC		0.11
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.27
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2063122901; hg19: chr2-214174875;