Genetic Variant SPIN3:p.Leu124Phe (chrX-56994576-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001010862.3(SPIN3):c.372G>C(p.Leu124Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

SPIN3
NM_001010862.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.171

Variant links:

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]

SPIN3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41096136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPIN3	NM_001010862.3 link	c.372G>C	p.Leu124Phe	missense_variant	Exon 2 of 2	ENST00000374919.6	NP_001010862.2	Q5JUX0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPIN3	ENST00000374919.6 link	c.372G>C	p.Leu124Phe	missense_variant	Exon 2 of 2	1	NM_001010862.3	ENSP00000364054.3		Q5JUX0-1
SPIN3	ENST00000639257.1 link	n.225+147G>C		intron_variant	Intron 2 of 4	3		ENSP00000492259.1		Q5JUX0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.372G>C (p.L124F) alteration is located in exon 2 (coding exon 1) of the SPIN3 gene. This alteration results from a G to C substitution at nucleotide position 372, causing the leucine (L) at amino acid position 124 to be replaced by a phenylalanine (F). 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

0.20

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.32

T;T;T;T;T;T

FATHMM_MKL

Benign

0.49

M_CAP

Benign

0.011

MetaRNN

Benign

0.41

T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.8

L;L;L;L;L;L

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

N;.;.;.;.;.

REVEL

Benign

0.27

Sift

Benign

0.072

T;.;.;.;.;.

Sift4G

Benign

0.081

T;.;.;.;.;.

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.36

MutPred

0.46

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.54

MPC

1.4

ClinPred

0.48

GERP RS

-0.51

Varity_R

0.39

gMVP

0.77

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over