chr11-76795938-C-T

Variant names:

• chr11-76795938-C-T
• rs141065796
• NM_015516.4:c.322C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_015516.4(TSKU):​c.322C>T​(p.Arg108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R108H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TSKU NM_015516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 17 AD gene.

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.322C>T	p.Arg108Cys	missense	Exon 2 of 2	NP_056331.2
	TSKU	NM_001318477.2		c.364C>T	p.Arg122Cys	missense	Exon 2 of 2	NP_001305406.1
	TSKU	NM_001258210.2		c.322C>T	p.Arg108Cys	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.322C>T	p.Arg108Cys	missense	Exon 2 of 2	ENSP00000332668.4	Q8WUA8
	TSKU	ENST00000527881.1	TSL:2	c.322C>T	p.Arg108Cys	missense	Exon 2 of 2	ENSP00000434847.1	Q8WUA8
	TSKU	ENST00000612930.1	TSL:4	c.322C>T	p.Arg108Cys	missense	Exon 2 of 2	ENSP00000482145.1	Q8WUA8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251082 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461634 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727136

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

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

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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	Benign	0.34
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.42		Loss of disorder (P = 0.0367)
MVP		0.41
MPC		1.4
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.59
Mutation Taster		=50/50

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: rs141065796; hg19: chr11-76506982; COSMIC: COSV60752663; COSMIC: COSV60752663;