11-76795924-C-A

Variant names:

• chr11-76795924-C-A
• rs1590821303
• NM_015516.4:c.308C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015516.4(TSKU):​c.308C>A​(p.Ala103Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A103V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSKU NM_015516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSKU	NM_015516.4	c.308C>A	p.Ala103Asp	missense_variant	Exon 2 of 2	ENST00000333090.5	NP_056331.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSKU	ENST00000333090.5	c.308C>A	p.Ala103Asp	missense_variant	Exon 2 of 2	1	NM_015516.4	ENSP00000332668.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.308C>A (p.A103D) alteration is located in exon 2 (coding exon 1) of the TSKU gene. This alteration results from a C to A substitution at nucleotide position 308, causing the alanine (A) at amino acid position 103 to be replaced by an aspartic acid (D). 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	0.60
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;T;.
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	.;L;L;.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.5	D;.;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;.;D;D;D
Sift4G	Uncertain	0.034	D;T;T;D;T
Polyphen		0.99	.;D;D;.;D
Vest4		0.59, 0.33
MutPred		0.65		Loss of catalytic residue at A103 (P = 0.043);Loss of catalytic residue at A103 (P = 0.043);Loss of catalytic residue at A103 (P = 0.043);Loss of catalytic residue at A103 (P = 0.043);Loss of catalytic residue at A103 (P = 0.043);
MVP		0.26
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		0.35
gMVP		0.81

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: rs1590821303; hg19: chr11-76506968;