rs201362069

Positions:

• chr21-44592378-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198688.3(KRTAP10-6):​c.107A>C​(p.Asp36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,521,062 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 24)
  • Exomes 𝑓: 0.0014 (92 hom.)
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.07

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063505173).
• BP6: Variant 21-44592378-T-G is Benign according to our data. Variant chr21-44592378-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 235482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00141 (1975/1405010) while in subpopulation AFR AF= 0.0197 (635/32256). AF 95% confidence interval is 0.0184. There are 92 homozygotes in gnomad4_exome. There are 943 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-6	NM_198688.3	c.107A>C	p.Asp36Ala	missense_variant	1/1	ENST00000400368.1	NP_941961.3
TSPEAR	NM_144991.3	c.83-24373A>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-24373A>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.107A>C	p.Asp36Ala	missense_variant	1/1	6	NM_198688.3	ENSP00000383219.1
TSPEAR	ENST00000323084.9	c.83-24373A>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-24373A>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 672 AN: 115942 Hom.: 7 Cov.: 24

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00326

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00102

Gnomad FIN AF: 0.000637

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00477

GnomAD3 exomes AF: 0.00946 AC: 2271 AN: 240130 Hom.: 3 AF XY: 0.00932 AC XY: 1211 AN XY: 129972

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.00280

Gnomad SAS exome AF: 0.00805

Gnomad FIN exome AF: 0.00542

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00874

GnomAD4 exome AF: 0.00141 AC: 1975 AN: 1405010 Hom.: 92 Cov.: 33 AF XY: 0.00135 AC XY: 943 AN XY: 696404

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.000450

Gnomad4 EAS exome AF: 0.000558

Gnomad4 SAS exome AF: 0.00277

Gnomad4 FIN exome AF: 0.000586

Gnomad4 NFE exome AF: 0.000792

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00580 AC: 673 AN: 116052 Hom.: 7 Cov.: 24 AF XY: 0.00574 AC XY: 317 AN XY: 55206

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00326

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00156

Gnomad4 SAS AF: 0.00102

Gnomad4 FIN AF: 0.000637

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.00469

Alfa AF: 0.0103 Hom.: 2

ESP6500AA AF: 0.0255 AC: 103

ESP6500EA AF: 0.0141 AC: 117

ExAC AF: 0.0115 AC: 1390

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 12, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Benign	0.93
Eigen	Benign	0.018
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.026	D
Sift4G	Benign	0.11	T
Vest4		0.15
MPC		0.60
ClinPred		0.035	T
GERP RS		2.2
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201362069; hg19: chr21-46012259; COSMIC: COSV59961818;