21-44646483-T-G

Position:

• chr21-44646483-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198692.3(KRTAP10-11):​c.25T>G​(p.Cys9Gly) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP10-11 NM_198692.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.605

Genes affected

KRTAP10-11 (HGNC:20528): (keratin associated protein 10-11) 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-11	NM_198692.3	c.25T>G	p.Cys9Gly	missense_variant	1/1	ENST00000334670.9	NP_941965.2
TSPEAR	NM_144991.3	c.82+64950A>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+44062A>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-11	ENST00000334670.9	c.25T>G	p.Cys9Gly	missense_variant	1/1	6	NM_198692.3	ENSP00000334197.8
TSPEAR	ENST00000323084.9	c.82+64950A>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+44062A>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 152

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

Oct 07, 2024

The c.25T>G (p.C9G) alteration is located in exon 1 (coding exon 1) of the KRTAP10-11 gene. This alteration results from a T to G substitution at nucleotide position 25, causing the cysteine (C) at amino acid position 9 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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.78
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.76		Gain of loop (P = 0.0312);
MVP		0.41
MPC		0.014
ClinPred		0.54	D
GERP RS		3.8
Varity_R		0.74
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr21-46066400;