rs115298124

Variant names:

• chr21-44637719-T-A
• rs115298124
• NM_181688.3:c.302T>A

Your query was ambiguous. Multiple possible variants found:

• chr21-44637719-T-A
• chr21-44637719-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181688.3(KRTAP10-10):​c.302T>A​(p.Val101Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,240,304 control chromosomes in the GnomAD database, including 1,277 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (620 hom., cov: 29)
  • Exomes 𝑓: 0.0082 (657 hom.)
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06
• Publications: 0 publications found

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]

TSPEAR Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021847188).
• BP6: Variant 21-44637719-T-A is Benign according to our data. Variant chr21-44637719-T-A is described in ClinVar as Benign. ClinVar VariationId is 377117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-10	NM_181688.3	c.302T>A	p.Val101Glu	missense_variant	Exon 1 of 1	ENST00000380095.2	NP_859016.1
TSPEAR	NM_144991.3	c.83-69714A>T		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+52826A>T		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-10	ENST00000380095.2	c.302T>A	p.Val101Glu	missense_variant	Exon 1 of 1	6	NM_181688.3	ENSP00000369438.1
TSPEAR	ENST00000323084.9	c.83-69714A>T		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+52826A>T		intron_variant	Intron 2 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.0584 AC: 7826 AN: 133960 Hom.: 610 Cov.: 29

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.00802

Gnomad EAS AF: 0.00125

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.000226

Gnomad MID AF: 0.0403

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.0485

GnomAD2 exomes AF: 0.0148 AC: 3692 AN: 250286 AF XY: 0.0113

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.00917

Gnomad ASJ exome AF: 0.00608

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00820 AC: 9066 AN: 1106236 Hom.: 657 Cov.: 110 AF XY: 0.00751 AC XY: 4109 AN XY: 547334

African (AFR) AF: 0.247 AC: 6311 AN: 25598

American (AMR) AF: 0.0177 AC: 498 AN: 28088

Ashkenazi Jewish (ASJ) AF: 0.00669 AC: 119 AN: 17792

East Asian (EAS) AF: 0.00168 AC: 61 AN: 36258

South Asian (SAS) AF: 0.0113 AC: 658 AN: 58452

European-Finnish (FIN) AF: 0.000355 AC: 15 AN: 42302

Middle Eastern (MID) AF: 0.0254 AC: 99 AN: 3898

European-Non Finnish (NFE) AF: 0.000528 AC: 448 AN: 848880

Other (OTH) AF: 0.0191 AC: 857 AN: 44968

GnomAD4 genome AF: 0.0587 AC: 7864 AN: 134068 Hom.: 620 Cov.: 29 AF XY: 0.0564 AC XY: 3671 AN XY: 65138

African (AFR) AF: 0.196 AC: 7281 AN: 37112

American (AMR) AF: 0.0251 AC: 340 AN: 13556

Ashkenazi Jewish (ASJ) AF: 0.00802 AC: 23 AN: 2868

East Asian (EAS) AF: 0.00125 AC: 6 AN: 4792

South Asian (SAS) AF: 0.0119 AC: 44 AN: 3706

European-Finnish (FIN) AF: 0.000226 AC: 2 AN: 8838

Middle Eastern (MID) AF: 0.0427 AC: 10 AN: 234

European-Non Finnish (NFE) AF: 0.00109 AC: 66 AN: 60380

Other (OTH) AF: 0.0502 AC: 92 AN: 1834

Alfa AF: 0.00634 Hom.: 12

Bravo AF: 0.0609

ESP6500AA AF: 0.125 AC: 550

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0202 AC: 2186

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.6
DANN	Benign	0.42
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.00020	N
LIST_S2	Benign	0.038	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.98	L
PhyloP100		-1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.012
Sift	Benign	0.23	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.19
MPC		0.073
ClinPred		0.0014	T
GERP RS		-5.7
Varity_R		0.085
gMVP		0.033
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115298124; hg19: chr21-46057636;