21-44637770-C-G

Position:

• chr21-44637770-C-G

Variant summary

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

The NM_181688.3(KRTAP10-10):​c.353C>G​(p.Thr118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0360

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 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=0.03811139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-10	NM_181688.3	c.353C>G	p.Thr118Ser	missense_variant	1/1	ENST00000380095.2	NP_859016.1
TSPEAR	NM_144991.3	c.83-69765G>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+52775G>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-10	ENST00000380095.2	c.353C>G	p.Thr118Ser	missense_variant	1/1	6	NM_181688.3	ENSP00000369438.1
TSPEAR	ENST00000323084.9	c.83-69765G>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+52775G>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1209428 Hom.: 0 Cov.: 120 AF XY: 0.00000499 AC XY: 3 AN XY: 601588

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: 0.00000325

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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 21, 2024

The c.353C>G (p.T118S) alteration is located in exon 1 (coding exon 1) of the KRTAP10-10 gene. This alteration results from a C to G substitution at nucleotide position 353, causing the threonine (T) at amino acid position 118 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	Benign	0.090
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.38
DANN	Benign	0.54
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.0047	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.019
Sift	Benign	0.49	T
Sift4G	Benign	0.56	T
Polyphen		0.032	B
Vest4		0.062
MutPred		0.35		Gain of phosphorylation at S123 (P = 0.1101);
MVP		0.24
MPC		0.045
ClinPred		0.028	T
GERP RS		-2.0
Varity_R		0.041
gMVP		0.025

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: chr21-46057687;