8-97276608-C-T

Position:

• chr8-97276608-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033512.3(TSPYL5):​c.1237G>A​(p.Val413Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSPYL5 NM_033512.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0110

Genes affected

TSPYL5 (HGNC:29367): (TSPY like 5) Predicted to enable chromatin binding activity and histone binding activity. Involved in several processes, including cellular response to gamma radiation; positive regulation of protein kinase B signaling; and positive regulation of protein ubiquitination. Predicted to be active in chromatin and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

LOC101927066 (HGNC:):

ACMG classification

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=0.06443405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPYL5	NM_033512.3	c.1237G>A	p.Val413Met	missense_variant	1/1	ENST00000322128.5	NP_277047.2
LOC101927066	NR_125390.1	n.471+142462G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPYL5	ENST00000322128.5	c.1237G>A	p.Val413Met	missense_variant	1/1	6	NM_033512.3	ENSP00000322802.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461210 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726888

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.1237G>A (p.V413M) alteration is located in exon 1 (coding exon 1) of the TSPYL5 gene. This alteration results from a G to A substitution at nucleotide position 1237, causing the valine (V) at amino acid position 413 to be replaced by a methionine (M). 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	0.094
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.086
Sift	Benign	0.053	T
Sift4G	Uncertain	0.044	D
Polyphen		0.53	P
Vest4		0.052
MutPred		0.074		Loss of catalytic residue at V413 (P = 0.0261);
MVP		0.20
MPC		0.63
ClinPred		0.22	T
GERP RS		0.48
Varity_R		0.029
gMVP		0.32

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

Other links and lift over

dbSNP: rs1810520745; hg19: chr8-98288836;