X-56994254-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010862.3. 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
	SPIN3	NM_001010862.3	MANE Select	c.694G>C	p.Val232Leu	missense	Exon 2 of 2	NP_001010862.2	Q5JUX0-1
	SPIN3	NR_027139.2		n.553+469G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPIN3	ENST00000374919.6	TSL:1 MANE Select	c.694G>C	p.Val232Leu	missense	Exon 2 of 2	ENSP00000364054.3	Q5JUX0-1
	SPIN3	ENST00000478405.1	TSL:1	n.225+469G>C		intron	N/A	ENSP00000433337.1	Q5JUX0-2
	SPIN3	ENST00000639257.1	TSL:3	n.225+469G>C		intron	N/A	ENSP00000492259.1	Q5JUX0-2

Frequencies

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

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

African (AFR) AF: 0.0000325 AC: 1 AN: 30734

American (AMR) AF: 0.00 AC: 0 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53164

Other (OTH) AF: 0.00 AC: 0 AN: 1505

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
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
Vest4		0.63
MutPred		0.76		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
Mutation Taster		=84/16	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: rs200340428; hg19: chrX-57020687;