21-44637440-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181688.3(KRTAP10-10):c.23T>C(p.Ile8Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0900

Genes affected

KRTAP10-10 (HGNC:22972): (keratin associated protein 10-10) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11181444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-10	NM_181688.3	c.23T>C	p.Ile8Thr	missense_variant	1/1	ENST00000380095.2
TSPEAR	NM_144991.3	c.83-69435A>G		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.-123+53105A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-10	ENST00000380095.2	c.23T>C	p.Ile8Thr	missense_variant	1/1		NM_181688.3	P1
TSPEAR	ENST00000323084.9	c.83-69435A>G		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*27+53105A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 29, 2023

The c.23T>C (p.I8T) alteration is located in exon 1 (coding exon 1) of the KRTAP10-10 gene. This alteration results from a T to C substitution at nucleotide position 23, causing the isoleucine (I) at amino acid position 8 to be replaced by a threonine (T). 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	0.33
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.93
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.081
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.063	T
Polyphen		0.067	B
Vest4		0.073
MutPred		0.49		Loss of sheet (P = 0.0457);
MVP		0.18
MPC		0.057
ClinPred		0.11	T
GERP RS		0.54
Varity_R		0.13
gMVP		0.024

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46057357;