21-44539333-C-G

Position:

• chr21-44539333-C-G

Variant summary

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

The ENST00000323084.9(TSPEAR):​c.304-5410G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSPEAR ENST00000323084.9 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0620

Genes affected

KRTAP10-1 (HGNC:22966): (keratin associated protein 10-1) This gene encodes a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This gene encodes a member of the high sulfur KAP family. It is localized to a cluster of intronless KAPs at 21q22.3 which are located within the introns of the C21orf29 gene. [provided by RefSeq, Jul 2008]

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]

TSPEAR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-1	NM_198691.3	c.818G>C	p.Cys273Ser	missense_variant	1/1	ENST00000400375.1	NP_941964.2
TSPEAR	NM_144991.3	c.304-5410G>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.100-5410G>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-1	ENST00000400375.1	c.818G>C	p.Cys273Ser	missense_variant	1/1	6	NM_198691.3	ENSP00000383226.1
TSPEAR	ENST00000323084.9	c.304-5410G>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.259-5410G>C		intron_variant		1
TSPEAR	ENST00000642437.1	n.*249-5410G>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 126

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

Mar 30, 2022

The c.818G>C (p.C273S) alteration is located in exon 1 (coding exon 1) of the KRTAP10-1 gene. This alteration results from a G to C substitution at nucleotide position 818, causing the cysteine (C) at amino acid position 273 to be replaced by a serine (S). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.53
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.17
Eigen_PC	Benign	-0.00073
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0047	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.18
MutPred		0.69		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.55
MPC		0.19
ClinPred		0.47	T
GERP RS		3.0
Varity_R		0.67
gMVP		0.065

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: chr21-45959216;