21-44592373-G-A

Position:

• chr21-44592373-G-A

Variant summary

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

The NM_198688.3(KRTAP10-6):​c.112C>T​(p.Pro38Ser) 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. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000014 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

Genes affected

KRTAP10-6 (HGNC:20523): (keratin associated protein 10-6) 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=0.27908263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-6	NM_198688.3	c.112C>T	p.Pro38Ser	missense_variant	1/1	ENST00000400368.1
TSPEAR	NM_144991.3	c.83-24368C>T		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.-122-24368C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.112C>T	p.Pro38Ser	missense_variant	1/1		NM_198688.3	P1
TSPEAR	ENST00000323084.9	c.83-24368C>T		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*28-24368C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000140 AC: 2 AN: 1430390 Hom.: 1 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 708120

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: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

May 08, 2023

The c.112C>T (p.P38S) alteration is located in exon 1 (coding exon 1) of the KRTAP10-6 gene. This alteration results from a C to T substitution at nucleotide position 112, causing the proline (P) at amino acid position 38 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	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.14	T
Vest4		0.25
MutPred		0.38		Gain of relative solvent accessibility (P = 0.0999);
MVP		0.41
MPC		0.49
ClinPred		0.71	D
GERP RS		3.5
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr21-46012254;