21-44627508-G-A

Position:

• chr21-44627508-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000323084.9(TSPEAR):​c.83-59503C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,381,420 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 0.000062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSPEAR ENST00000323084.9 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.923

Genes affected

KRTAP10-9 (HGNC:22971): (keratin associated protein 10-9) 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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013977379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-9	NM_198690.3	c.337G>A	p.Val113Ile	missense_variant	1/1	ENST00000397911.5	NP_941963.2
TSPEAR	NM_144991.3	c.83-59503C>T		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-59503C>T		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-9	ENST00000397911.5	c.337G>A	p.Val113Ile	missense_variant	1/1		NM_198690.3	ENSP00000381009	P1
TSPEAR	ENST00000323084.9	c.83-59503C>T		intron_variant		1	NM_144991.3	ENSP00000321987	P1
KRTAP10-9	ENST00000484861.1	n.226+160G>A		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*28-59503C>T		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9 AN: 144580 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00125

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000302

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250628 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000297 AC: 41 AN: 1381420 Hom.: 0 Cov.: 151 AF XY: 0.0000278 AC XY: 19 AN XY: 684608

Gnomad4 AFR exome AF: 0.0000333

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000626

Gnomad4 SAS exome AF: 0.0000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000934

Gnomad4 OTH exome AF: 0.0000709

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000622 AC: 9 AN: 144692 Hom.: 0 Cov.: 32 AF XY: 0.0000852 AC XY: 6 AN XY: 70438

Gnomad4 AFR AF: 0.0000258

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00126

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000302

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ExAC AF: 0.0000824 AC: 10

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 28, 2023

The c.337G>A (p.V113I) alteration is located in exon 1 (coding exon 1) of the KRTAP10-9 gene. This alteration results from a G to A substitution at nucleotide position 337, causing the valine (V) at amino acid position 113 to be replaced by an isoleucine (I). 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	0.079
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.49
DANN	Benign	0.79
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.028	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.48	N;.
REVEL	Benign	0.025
Sift	Benign	0.26	T;.
Sift4G	Benign	0.30	T;T
Polyphen		0.0040	B;.
Vest4		0.031
MutPred		0.44		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.055
ClinPred		0.020	T
GERP RS		-0.86
Varity_R		0.020
gMVP		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781784058; hg19: chr21-46047425;