2-200416405-T-C

Position:

• chr2-200416405-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001100423.2(SPATS2L):​c.175T>C​(p.Trp59Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000668 in 1,347,098 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: 32)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: SPATS2L NM_001100423.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49

Genes affected

SPATS2L (HGNC:24574): (spermatogenesis associated serine rich 2 like) Enables RNA binding activity. Located in cytosol; nucleolus; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000287299 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATS2L	NM_001100423.2	c.175T>C	p.Trp59Arg	missense_variant	5/13	ENST00000409140.8	NP_001093893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATS2L	ENST00000409140.8	c.175T>C	p.Trp59Arg	missense_variant	5/13	2	NM_001100423.2	ENSP00000386730.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000668 AC: 9 AN: 1347098 Hom.: 0 Cov.: 21 AF XY: 0.00000599 AC XY: 4 AN XY: 668196

Gnomad4 AFR exome AF: 0.0000334

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000576

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2024

The c.175T>C (p.W59R) alteration is located in exon 5 (coding exon 3) of the SPATS2L gene. This alteration results from a T to C substitution at nucleotide position 175, causing the tryptophan (W) at amino acid position 59 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;T;T;.;T;T;T;T;T;.;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.7	.;M;M;M;.;M;M;.;.;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-13	D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;.;D;D;.;.;.;D;.;.;.;.;.;.
Vest4		0.97, 0.94, 0.98, 0.98
MutPred		0.75		Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);.;.;Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);.;
MVP		0.59
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1413989554; hg19: chr2-201281128;