rs61029972

Variant names:

• chr21-44637717-T-C
• rs61029972
• NM_181688.3:c.300T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181688.3(KRTAP10-10):​c.300T>C​(p.Cys100Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 848,560 control chromosomes in the GnomAD database, including 1,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (627 hom., cov: 16)
  • Exomes 𝑓: 0.012 (669 hom.)
• Consequence: KRTAP10-10 NM_181688.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

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

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 21-44637717-T-C is Benign according to our data. Variant chr21-44637717-T-C is described in ClinVar as Benign. ClinVar VariationId is 403022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.038 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181688.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-10	NM_181688.3	MANE Select	c.300T>C	p.Cys100Cys	synonymous	Exon 1 of 1	NP_859016.1	P60014
	TSPEAR	NM_144991.3	MANE Select	c.83-69712A>G		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+52828A>G		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-10	ENST00000380095.2	TSL:6 MANE Select	c.300T>C	p.Cys100Cys	synonymous	Exon 1 of 1	ENSP00000369438.1	P60014
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-69712A>G		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-69712A>G		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 7853 AN: 70116 Hom.: 617 Cov.: 16

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00238

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.000739

Gnomad MID AF: 0.116

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.0946

GnomAD2 exomes AF: 0.0178 AC: 3724 AN: 208662 AF XY: 0.0135

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00687

Gnomad EAS exome AF: 0.00301

Gnomad FIN exome AF: 0.000273

Gnomad NFE exome AF: 0.000956

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0118 AC: 9156 AN: 778370 Hom.: 669 Cov.: 93 AF XY: 0.0106 AC XY: 4151 AN XY: 390226

African (AFR) AF: 0.287 AC: 6329 AN: 22028

American (AMR) AF: 0.0241 AC: 499 AN: 20690

Ashkenazi Jewish (ASJ) AF: 0.00928 AC: 120 AN: 12928

East Asian (EAS) AF: 0.00212 AC: 65 AN: 30604

South Asian (SAS) AF: 0.0133 AC: 671 AN: 50574

European-Finnish (FIN) AF: 0.000522 AC: 18 AN: 34488

Middle Eastern (MID) AF: 0.0343 AC: 100 AN: 2916

European-Non Finnish (NFE) AF: 0.000867 AC: 495 AN: 571178

Other (OTH) AF: 0.0261 AC: 859 AN: 32964

GnomAD4 genome AF: 0.112 AC: 7891 AN: 70190 Hom.: 627 Cov.: 16 AF XY: 0.108 AC XY: 3683 AN XY: 34236

African (AFR) AF: 0.324 AC: 7295 AN: 22494

American (AMR) AF: 0.0561 AC: 341 AN: 6074

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 23 AN: 1280

East Asian (EAS) AF: 0.00239 AC: 7 AN: 2926

South Asian (SAS) AF: 0.0190 AC: 45 AN: 2372

European-Finnish (FIN) AF: 0.000739 AC: 3 AN: 4060

Middle Eastern (MID) AF: 0.116 AC: 10 AN: 86

European-Non Finnish (NFE) AF: 0.00254 AC: 75 AN: 29566

Other (OTH) AF: 0.0973 AC: 92 AN: 946

Alfa AF: 0.155 Hom.: 52

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.0
DANN	Benign	0.33
PhyloP100		0.038
PromoterAI		0.031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61029972; hg19: chr21-46057634; COSMIC: COSV59951487;