21-44591464-C-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.1021G>C(p.Val341Leu) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

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=0.116965115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-6	NM_198688.3	c.1021G>C	p.Val341Leu	missense_variant	1/1	ENST00000400368.1
TSPEAR	NM_144991.3	c.83-23459G>C		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.-122-23459G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.1021G>C	p.Val341Leu	missense_variant	1/1		NM_198688.3	P1
TSPEAR	ENST00000323084.9	c.83-23459G>C		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*28-23459G>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

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

May 05, 2023

The c.1021G>C (p.V341L) alteration is located in exon 1 (coding exon 1) of the KRTAP10-6 gene. This alteration results from a G to C substitution at nucleotide position 1021, causing the valine (V) at amino acid position 341 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.077	N
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.098
Sift	Benign	0.051	T
Sift4G	Benign	0.17	T
Vest4		0.042
MutPred		0.23		Loss of sheet (P = 0.0457);
MVP		0.14
MPC		0.93
ClinPred		0.42	T
GERP RS		1.9
gMVP		0.056

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46011345;