Genetic Variant NM_021648.5:c.1178G>A (chr6-116252831-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021648.5(TSPYL4):c.1178G>A(p.Arg393Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,446,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TSPYL4
NM_021648.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.41

Publications

0 publications found

Variant links:

Genes affected

TSPYL4 (HGNC:21559): (TSPY like 4) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in nucleosome assembly. Predicted to be active in chromatin and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TSPYL4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22410884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPYL4	NM_021648.5 link	c.1178G>A	p.Arg393Lys	missense_variant	Exon 1 of 1	ENST00000420283.3	NP_067680.3	Q9UJ04

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPYL4	ENST00000420283.3 link	c.1178G>A	p.Arg393Lys	missense_variant	Exon 1 of 1	6	NM_021648.5	ENSP00000410943.1		Q9UJ04

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000135

AC:

AN:

221416

AF XY:

0.0000167

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000187

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1446070

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717754

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33186

American (AMR)

AF:

0.00

AC:

AN:

42246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25786

East Asian (EAS)

AF:

0.0000766

AC:

AN:

39184

South Asian (SAS)

AF:

0.00

AC:

AN:

83900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103788

Other (OTH)

AF:

0.00

AC:

AN:

59860

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000042), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1178G>A (p.R393K) alteration is located in exon 1 (coding exon 1) of the TSPYL4 gene. This alteration results from a G to A substitution at nucleotide position 1178, causing the arginine (R) at amino acid position 393 to be replaced by a lysine (K). 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

0.14

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.52

M_CAP

Benign

0.0052

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

4.4

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.7

REVEL

Benign

0.085

Sift

Uncertain

0.015

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.18

MutPred

0.34

Gain of methylation at R393 (P = 0.0056);

MVP

0.87

MPC

0.84

ClinPred

0.69

GERP RS

3.7

Varity_R

0.34

gMVP

0.38

Mutation Taster

=96/4

polymorphism

(source)

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

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NM_021648.5:c.1178G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over