X-56994823-G-A

Variant names:

• chrX-56994823-G-A
• rs780110899
• NM_001010862.3:c.125C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001010862.3(SPIN3):​c.125C>T​(p.Thr42Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,209,791 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: SPIN3 NM_001010862.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00200

Genes affected

SPIN3 (HGNC:27272): (spindlin family member 3) Enables methylated histone binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be integral component of membrane. Predicted to be active in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03525105).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPIN3	NM_001010862.3	c.125C>T	p.Thr42Ile	missense_variant	Exon 2 of 2	ENST00000374919.6	NP_001010862.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPIN3	ENST00000374919.6	c.125C>T	p.Thr42Ile	missense_variant	Exon 2 of 2	1	NM_001010862.3	ENSP00000364054.3
SPIN3	ENST00000639257.1	n.125C>T		non_coding_transcript_exon_variant	Exon 2 of 5	3		ENSP00000492259.1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111543 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33731

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 182075 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67637

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1098248 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111543 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33731

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125C>T (p.T42I) alteration is located in exon 2 (coding exon 1) of the SPIN3 gene. This alteration results from a C to T substitution at nucleotide position 125, causing the threonine (T) at amino acid position 42 to be replaced by an isoleucine (I). 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	Benign	0.070
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.6
DANN	Benign	0.23
DEOGEN2	Benign	0.052	T;T;T;T;.;T;T;.;.;.
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.13	.;.;.;.;T;.;.;T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.035	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N;N;N;.;N;N;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.60	N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.019
Sift	Benign	0.46	T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.51	T;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;B;B;B;.;B;B;.;.;.
Vest4		0.080
MutPred		0.26		Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);Loss of glycosylation at T42 (P = 0.0042);
MVP		0.068
MPC		0.51
ClinPred		0.030	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs780110899; hg19: chrX-57021256;