6-116253136-T-G

Variant names:

• chr6-116253136-T-G
• rs745428647
• NM_021648.5:c.873A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021648.5(TSPYL4):​c.873A>C​(p.Arg291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPYL4 NM_021648.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.179
• Publications: 0 publications found

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]

ACMG classification

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=0.24484828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPYL4	NM_021648.5	c.873A>C	p.Arg291Ser	missense_variant	Exon 1 of 1	ENST00000420283.3	NP_067680.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPYL4	ENST00000420283.3	c.873A>C	p.Arg291Ser	missense_variant	Exon 1 of 1	6	NM_021648.5	ENSP00000410943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249392 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.873A>C (p.R291S) alteration is located in exon 1 (coding exon 1) of the TSPYL4 gene. This alteration results from a A to C substitution at nucleotide position 873, causing the arginine (R) at amino acid position 291 to be replaced by a serine (S). 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	0.88
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.18
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.21	T
Polyphen		0.62	P
Vest4		0.29
MutPred		0.40		Loss of solvent accessibility (P = 0.0606);
MVP		0.64
MPC		1.2
ClinPred		0.93	D
GERP RS		0.14
Varity_R		0.42
gMVP		0.33
Mutation Taster		=88/12	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: rs745428647; hg19: chr6-116574299;