21-44637719-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181688.3(KRTAP10-10):​c.302T>C​(p.Val101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,240,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V101E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 29)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032742918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-10	NM_181688.3	c.302T>C	p.Val101Ala	missense_variant	Exon 1 of 1	ENST00000380095.2	NP_859016.1
TSPEAR	NM_144991.3	c.83-69714A>G		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-123+52826A>G		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>C	p.Val101Ala	missense_variant	Exon 1 of 1	6	NM_181688.3	ENSP00000369438.1
TSPEAR	ENST00000323084.9	c.83-69714A>G		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*27+52826A>G		intron_variant	Intron 2 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.00000746 AC: 1 AN: 134064 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.04e-7 AC: 1 AN: 1106268 Hom.: 0 Cov.: 110 AF XY: 0.00000183 AC XY: 1 AN XY: 547346

African (AFR) AF: 0.00 AC: 0 AN: 25624

American (AMR) AF: 0.00 AC: 0 AN: 28088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17792

East Asian (EAS) AF: 0.00 AC: 0 AN: 36260

South Asian (SAS) AF: 0.0000171 AC: 1 AN: 58452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 848884

Other (OTH) AF: 0.00 AC: 0 AN: 44968

GnomAD4 genome AF: 0.00000746 AC: 1 AN: 134064 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 65080

African (AFR) AF: 0.00 AC: 0 AN: 37100

American (AMR) AF: 0.00 AC: 0 AN: 13540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2868

East Asian (EAS) AF: 0.00 AC: 0 AN: 4806

South Asian (SAS) AF: 0.000269 AC: 1 AN: 3712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60390

Other (OTH) AF: 0.00 AC: 0 AN: 1814

Alfa AF: 0.00 Hom.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.6
DANN	Benign	0.45
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.028	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.1
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.016
Sift	Benign	0.10	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.084
MutPred		0.52		Gain of sheet (P = 0.1208);
MVP		0.030
MPC		0.055
ClinPred		0.083	T
GERP RS		-5.7
PromoterAI		-0.00080	Neutral
Varity_R		0.020
gMVP		0.031
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;