21-44638127-G-T

Variant names:

• chr21-44638127-G-T
• rs143765249
• NM_181688.3:c.710G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181688.3(KRTAP10-10):​c.710G>T​(p.Arg237Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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. R237H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 27)
• Consequence: KRTAP10-10 NM_181688.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18383598).

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.710G>T	p.Arg237Leu	missense	Exon 1 of 1	NP_859016.1	P60014
	TSPEAR	NM_144991.3	MANE Select	c.83-70122C>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+52418C>A		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.710G>T	p.Arg237Leu	missense	Exon 1 of 1	ENSP00000369438.1	P60014
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-70122C>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-70122C>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.073	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		-0.013
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		0.80	P
Vest4		0.14
MutPred		0.26		Gain of sheet (P = 0.1945)
MVP		0.17
MPC		0.063
ClinPred		0.85	D
GERP RS		1.5
Varity_R		0.25
gMVP		0.059
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143765249; hg19: chr21-46058044;