NM_015516.4:c.412C>T

Variant names:

• chr11-76796028-C-T
• NM_015516.4:c.412C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015516.4(TSKU):​c.412C>T​(p.Leu138Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: TSKU NM_015516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06
• Publications: 0 publications found

Genes affected

TSKU (HGNC:28850): (tsukushi, small leucine rich proteoglycan) Predicted to enable transforming growth factor beta binding activity. Predicted to be involved in several processes, including animal organ development; cholesterol efflux; and cholesterol homeostasis. Predicted to act upstream of or within several processes, including ciliary body morphogenesis; negative regulation of Wnt signaling pathway; and telencephalon development. Predicted to be located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSKU	NM_015516.4	MANE Select	c.412C>T	p.Leu138Phe	missense	Exon 2 of 2	NP_056331.2
	TSKU	NM_001318477.2		c.454C>T	p.Leu152Phe	missense	Exon 2 of 2	NP_001305406.1
	TSKU	NM_001258210.2		c.412C>T	p.Leu138Phe	missense	Exon 2 of 2	NP_001245139.1	Q8WUA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSKU	ENST00000333090.5	TSL:1 MANE Select	c.412C>T	p.Leu138Phe	missense	Exon 2 of 2	ENSP00000332668.4	Q8WUA8
	TSKU	ENST00000527881.1	TSL:2	c.412C>T	p.Leu138Phe	missense	Exon 2 of 2	ENSP00000434847.1	Q8WUA8
	TSKU	ENST00000612930.1	TSL:4	c.412C>T	p.Leu138Phe	missense	Exon 2 of 2	ENSP00000482145.1	Q8WUA8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.73		Gain of catalytic residue at L138 (P = 0.0969)
MVP		0.39
MPC		1.3
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.62
gMVP		0.76
Mutation Taster		=43/57	disease causing

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

hg19: chr11-76507072;