21-44637508-T-G

Position:

• chr21-44637508-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181688.3(KRTAP10-10):​c.91T>G​(p.Cys31Gly) 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 benign outcome for this variant. 13/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.564

Genes affected

KRTAP10-10 (HGNC:22972): (keratin associated protein 10-10) 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32646644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-10	NM_181688.3	c.91T>G	p.Cys31Gly	missense_variant	1/1	ENST00000380095.2	NP_859016.1
TSPEAR	NM_144991.3	c.83-69503A>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+53037A>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-10	ENST00000380095.2	c.91T>G	p.Cys31Gly	missense_variant	1/1	6	NM_181688.3	ENSP00000369438.1
TSPEAR	ENST00000323084.9	c.83-69503A>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+53037A>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461028 Hom.: 0 Cov.: 131 AF XY: 0.00 AC XY: 0 AN XY: 726842

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 31, 2023

The c.91T>G (p.C31G) alteration is located in exon 1 (coding exon 1) of the KRTAP10-10 gene. This alteration results from a T to G substitution at nucleotide position 91, causing the cysteine (C) at amino acid position 31 to be replaced by a glycine (G). 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	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Benign	0.15
Sift	Benign	0.087	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.014	B
Vest4		0.28
MutPred		0.72		Loss of stability (P = 0.0725);
MVP		0.26
MPC		0.056
ClinPred		0.17	T
GERP RS		0.19
Varity_R		0.39
gMVP		0.14

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: chr21-46057425;