Genetic Variant NM_001012968.3:c.621T>A (chrX-63350199-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001012968.3(SPIN4):c.621T>A(p.His207Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,209,973 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 1 hem. )

Consequence

SPIN4
NM_001012968.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.153

Variant links:

Genes affected

SPIN4 (HGNC:27040): (spindlin family member 4) Enables methylated histone binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be active in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SPIN4 links:

SPIN4-AS1 (HGNC:41177): (SPIN4 antisense RNA 1)

SPIN4-AS1 links:

LINC01278 (HGNC:28090): (long intergenic non-protein coding RNA 1278)

LINC01278 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.063652694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPIN4	NM_001012968.3 link	c.621T>A	p.His207Gln	missense_variant	Exon 1 of 1	ENST00000374884.3	NP_001012986.2	Q56A73
SPIN4-AS1	NR_046739.1 link	n.298+465A>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPIN4	ENST00000374884.3 link	c.621T>A	p.His207Gln	missense_variant	Exon 1 of 1	6	NM_001012968.3	ENSP00000364018.3		Q56A73

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111745

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33935

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

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:

0.000664

GnomAD3 exomes

AF:

0.0000605

AC:

AN:

181833

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67657

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000402

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1098175

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363533

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000398

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33998

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000284

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:

0.000656

Bravo

AF:

0.0000453

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.621T>A (p.H207Q) alteration is located in exon 1 (coding exon 1) of the SPIN4 gene. This alteration results from a T to A substitution at nucleotide position 621, causing the histidine (H) at amino acid position 207 to be replaced by a glutamine (Q). 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

0.63

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.031

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.85

M_CAP

Benign

0.010

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.66

REVEL

Benign

0.15

Polyphen

0.017

MutPred

0.56

Gain of helix (P = 0.0225);

MVP

0.41

ClinPred

0.13

GERP RS

-2.4

Varity_R

0.76

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over