21-44579849-C-T

Position:

• chr21-44579849-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000323084.9(TSPEAR):​c.83-11844G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,594,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: TSPEAR ENST00000323084.9 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.93

Genes affected

KRTAP10-5 (HGNC:22969): (keratin associated protein 10-5) This is an intronless gene located in a cluster of related genes on the q arm of chromosome 21. The proteins encoded by these genes form disulfide bonds with cysteine residues in hair keratins, thereby contributing to the structure and stability of hair fibers. [provided by RefSeq, Apr 2014]

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029575408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-5	NM_198694.3	c.730G>A	p.Ala244Thr	missense_variant	1/1	ENST00000400372.1	NP_941967.3
TSPEAR	NM_144991.3	c.83-11844G>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-11844G>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-5	ENST00000400372.1	c.730G>A	p.Ala244Thr	missense_variant	1/1	6	NM_198694.3	ENSP00000383223.1
TSPEAR	ENST00000323084.9	c.83-11844G>A		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-11844G>A		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151782 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000561 AC: 14 AN: 249742 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135314

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000457 AC: 66 AN: 1443060 Hom.: 0 Cov.: 113 AF XY: 0.0000362 AC XY: 26 AN XY: 718028

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000947

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000409

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151900 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74252

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000678 Hom.: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 30, 2022

The c.730G>A (p.A244T) alteration is located in exon 1 (coding exon 1) of the KRTAP10-5 gene. This alteration results from a G to A substitution at nucleotide position 730, causing the alanine (A) at amino acid position 244 to be replaced by a threonine (T). 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
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.015
DANN	Benign	0.68
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.038
Sift	Benign	0.62	T
Sift4G	Benign	0.83	T
Vest4		0.030
MutPred		0.27		Gain of glycosylation at A244 (P = 0.0348);
MVP		0.030
MPC		0.12
ClinPred		0.026	T
GERP RS		1.1
gMVP		0.030

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587629437; hg19: chr21-45999726;