chr21-44612161-T-C

Position:

• chr21-44612161-T-C

Variant summary

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

The NM_198695.2(KRTAP10-8):​c.61T>C​(p.Ser21Pro) 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: 32)
• Consequence: KRTAP10-8 NM_198695.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

KRTAP10-8 (HGNC:20525): (keratin associated protein 10-8) Enables identical protein binding activity. 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, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-8	NM_198695.2	c.61T>C	p.Ser21Pro	missense_variant	1/1	ENST00000334662.2	NP_941968.2
TSPEAR	NM_144991.3	c.83-44156A>G		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-44156A>G		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-8	ENST00000334662.2	c.61T>C	p.Ser21Pro	missense_variant	1/1	6	NM_198695.2	ENSP00000335565.2
TSPEAR	ENST00000323084.9	c.83-44156A>G		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-44156A>G		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 10, 2024

The c.61T>C (p.S21P) alteration is located in exon 1 (coding exon 1) of the KRTAP10-8 gene. This alteration results from a T to C substitution at nucleotide position 61, causing the serine (S) at amino acid position 21 to be replaced by a proline (P). 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	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0083	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.19
Sift	Uncertain	0.024	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.67		Gain of sheet (P = 0.0085);
MVP		0.65
MPC		0.38
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.75
gMVP		0.19

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: chr21-46032078;