21-44592318-A-C

Variant names:

• chr21-44592318-A-C
• rs202093454
• NM_198688.3:c.167T>G

Variant summary

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

The NM_198688.3(KRTAP10-6):​c.167T>G​(p.Val56Gly) 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 9)
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

KRTAP10-6 (HGNC:20523): (keratin associated protein 10-6) 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=0.17708066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-6	NM_198688.3	c.167T>G	p.Val56Gly	missense_variant	Exon 1 of 1	ENST00000400368.1	NP_941961.3
TSPEAR	NM_144991.3	c.83-24313T>G		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-24313T>G		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.167T>G	p.Val56Gly	missense_variant	Exon 1 of 1	6	NM_198688.3	ENSP00000383219.1
TSPEAR	ENST00000323084.9	c.83-24313T>G		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-24313T>G		intron_variant	Intron 2 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 9

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.167T>G (p.V56G) alteration is located in exon 1 (coding exon 1) of the KRTAP10-6 gene. This alteration results from a T to G substitution at nucleotide position 167, causing the valine (V) at amino acid position 56 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.015	N
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.039
Sift	Benign	0.033	D
Sift4G	Uncertain	0.0020	D
Vest4		0.19
MutPred		0.45		Loss of stability (P = 0.0021);
MVP		0.30
MPC		0.63
ClinPred		0.64	D
GERP RS		0.20
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202093454; hg19: chr21-46012199;