21-44539414-A-T

Position:

• chr21-44539414-A-T

Variant summary

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

The NM_198691.3(KRTAP10-1):​c.737T>A​(p.Met246Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,450,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KRTAP10-1 NM_198691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.647

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]

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.737T>A	p.Met246Lys	missense_variant	1/1	ENST00000400375.1	NP_941964.2
TSPEAR	NM_144991.3	c.304-5491T>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.100-5491T>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-1	ENST00000400375.1	c.737T>A	p.Met246Lys	missense_variant	1/1		NM_198691.3	ENSP00000383226	P1
TSPEAR	ENST00000323084.9	c.304-5491T>A		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.259-5491T>A		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*249-5491T>A		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250434 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1450638 Hom.: 0 Cov.: 127 AF XY: 0.00000693 AC XY: 5 AN XY: 721952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000633 Hom.: 0

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

Jun 17, 2024

The c.737T>A (p.M246K) alteration is located in exon 1 (coding exon 1) of the KRTAP10-1 gene. This alteration results from a T to A substitution at nucleotide position 737, causing the methionine (M) at amino acid position 246 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.69
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.044	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.26	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.015
Sift	Benign	0.16	T
Sift4G	Benign	0.61	T
Polyphen		0.0040	B
Vest4		0.20
MutPred		0.36		Gain of methylation at M246 (P = 6e-04);
MVP		0.067
MPC		0.24
ClinPred		0.032	T
GERP RS		0.20
Varity_R		0.17
gMVP		0.050

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555916824; hg19: chr21-45959297;