X-56994254-C-G

Variant names:

• chrX-56994254-C-G
• rs200340428
• NM_001010862.3:c.694G>C

Variant summary

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

The NM_001010862.3(SPIN3):​c.694G>C​(p.Val232Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000894 in 111,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: SPIN3 NM_001010862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13

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 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, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPIN3	NM_001010862.3	c.694G>C	p.Val232Leu	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.694G>C	p.Val232Leu	missense_variant	Exon 2 of 2	1	NM_001010862.3	ENSP00000364054.3
SPIN3	ENST00000639257.1	n.225+469G>C		intron_variant	Intron 2 of 4	3		ENSP00000492259.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111807 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33973

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111807 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33973

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.0069	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	.;.;.;.;.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;.;.;.;.;.;.
Sift4G	Uncertain	0.013	D;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.63
MutPred		0.76		Gain of catalytic residue at V232 (P = 0.0784);Gain of catalytic residue at V232 (P = 0.0784);Gain of catalytic residue at V232 (P = 0.0784);Gain of catalytic residue at V232 (P = 0.0784);Gain of catalytic residue at V232 (P = 0.0784);Gain of catalytic residue at V232 (P = 0.0784);.;
MVP		0.64
MPC		1.4
ClinPred		0.97	D
GERP RS		2.7
Varity_R		0.69
gMVP		0.83

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: rs200340428; hg19: chrX-57020687;