21-44592114-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_198688.3(KRTAP10-6):c.371G>A(p.Cys124Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0011 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.436

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008411974).
• BP6: Variant 21-44592114-C-T is Benign according to our data. Variant chr21-44592114-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2578916.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-6	NM_198688.3	c.371G>A	p.Cys124Tyr	missense_variant	1/1	ENST00000400368.1
TSPEAR	NM_144991.3	c.83-24109G>A		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.-122-24109G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.371G>A	p.Cys124Tyr	missense_variant	1/1		NM_198688.3	P1
TSPEAR	ENST00000323084.9	c.83-24109G>A		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*28-24109G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 85 AN: 112414 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000505

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000539

Gnomad OTH AF: 0.00254

GnomAD3 exomes AF: 0.00411 AC: 906 AN: 220452 Hom.: 1 AF XY: 0.00376 AC XY: 451 AN XY: 120090

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00284

Gnomad EAS exome AF: 0.0131

Gnomad SAS exome AF: 0.00217

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.00338

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00107 AC: 1396 AN: 1303552 Hom.: 8 Cov.: 36 AF XY: 0.000951 AC XY: 617 AN XY: 648846

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.000518

Gnomad4 EAS exome AF: 0.000814

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.000900

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000747 AC: 84 AN: 112492 Hom.: 0 Cov.: 19 AF XY: 0.000790 AC XY: 43 AN XY: 54412

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.000505

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000539

Gnomad4 OTH AF: 0.00250

Alfa AF: 0.0244 Hom.: 0

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

KRTAP10-6: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Benign	0.81
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.17
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.012	D
Vest4		0.27
MVP		0.26
MPC		0.82
ClinPred		0.045	T
GERP RS		2.7
gMVP		0.35

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: rs199595314; hg19: chr21-46011995; COSMIC: COSV59954808;