rs76743925

Positions:

• chr21-44637665-A-C

Variant summary

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

The NM_181688.3(KRTAP10-10):​c.248A>C​(p.Asp83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,574,330 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (67 hom.)
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0100

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061335564).
• BP6: Variant 21-44637665-A-C is Benign according to our data. Variant chr21-44637665-A-C is described in ClinVar as [Benign]. Clinvar id is 377201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2199/148694) while in subpopulation AFR AF= 0.0506 (2017/39846). AF 95% confidence interval is 0.0488. There are 38 homozygotes in gnomad4. There are 1005 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-10	NM_181688.3	c.248A>C	p.Asp83Ala	missense_variant	1/1	ENST00000380095.2	NP_859016.1
TSPEAR	NM_144991.3	c.83-69660T>G		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+52880T>G		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-10	ENST00000380095.2	c.248A>C	p.Asp83Ala	missense_variant	1/1	6	NM_181688.3	ENSP00000369438.1
TSPEAR	ENST00000323084.9	c.83-69660T>G		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+52880T>G		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2191 AN: 148578 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00546

Gnomad ASJ AF: 0.00639

Gnomad EAS AF: 0.000400

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0200

Gnomad NFE AF: 0.000729

Gnomad OTH AF: 0.0103

GnomAD3 exomes AF: 0.00397 AC: 996 AN: 250568 Hom.: 21 AF XY: 0.00295 AC XY: 400 AN XY: 135510

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00164 AC: 2340 AN: 1425636 Hom.: 67 Cov.: 135 AF XY: 0.00150 AC XY: 1063 AN XY: 708420

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.00352

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.000230

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.0148 AC: 2199 AN: 148694 Hom.: 38 Cov.: 33 AF XY: 0.0139 AC XY: 1005 AN XY: 72534

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.00545

Gnomad4 ASJ AF: 0.00639

Gnomad4 EAS AF: 0.000401

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000714

Gnomad4 OTH AF: 0.0102

Alfa AF: 0.00945 Hom.: 17

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00500 AC: 607

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 29, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.019
DANN	Benign	0.40
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00015	N
LIST_S2	Benign	0.0091	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.9	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	4.2	N
REVEL	Benign	0.047
Sift	Benign	0.94	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.037
MVP		0.12
MPC		0.056
ClinPred		0.0073	T
GERP RS		0.25
Varity_R		0.044
gMVP		0.042

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs76743925; hg19: chr21-46057582; COSMIC: COSV59965807;