21-44612500-T-G

Variant names:

• chr21-44612500-T-G
• rs140050455
• NM_198695.2:c.400T>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_198695.2(KRTAP10-8):​c.400T>G​(p.Cys134Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00747 in 1,611,440 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (51 hom.)
• Consequence: KRTAP10-8 NM_198695.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0250

Genes affected

KRTAP10-8 (HGNC:20525): (keratin associated protein 10-8) Enables identical protein binding activity. 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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008698702).
• BP6: Variant 21-44612500-T-G is Benign according to our data. Variant chr21-44612500-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3770419.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-8	NM_198695.2	c.400T>G	p.Cys134Gly	missense_variant	Exon 1 of 1	ENST00000334662.2	NP_941968.2
TSPEAR	NM_144991.3	c.83-44495A>C		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-44495A>C		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-8	ENST00000334662.2	c.400T>G	p.Cys134Gly	missense_variant	Exon 1 of 1	6	NM_198695.2	ENSP00000335565.2
TSPEAR	ENST00000323084.9	c.83-44495A>C		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-44495A>C		intron_variant	Intron 2 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 902 AN: 151662 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00912

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00602 AC: 1514 AN: 251328 Hom.: 6 AF XY: 0.00572 AC XY: 777 AN XY: 135840

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00869

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00763 AC: 11140 AN: 1459660 Hom.: 51 Cov.: 35 AF XY: 0.00750 AC XY: 5445 AN XY: 726160

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00693

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.00868

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00594 AC: 902 AN: 151780 Hom.: 3 Cov.: 32 AF XY: 0.00554 AC XY: 411 AN XY: 74202

Gnomad4 AFR AF: 0.00177

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.00912

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00767 Hom.: 4

Bravo AF: 0.00495

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00662 AC: 804

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00687

EpiControl AF: 0.00640

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KRTAP10-8: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.44
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.74	P
Vest4		0.42
MVP		0.35
MPC		0.076
ClinPred		0.079	T
GERP RS		2.3
Varity_R		0.22
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140050455; hg19: chr21-46032417; COSMIC: COSV99080089;