21-44551077-G-T

Variant names:

• chr21-44551077-G-T
• rs374542929
• NM_198693.4:c.382C>A

Variant summary

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

The NM_198693.4(KRTAP10-2):​c.382C>A​(p.Pro128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P128A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRTAP10-2 NM_198693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

Genes affected

KRTAP10-2 (HGNC:22967): (keratin associated protein 10-2) This gene encodes a member of the high sulfur-type keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. This gene is located in a cluster of similar genes on 21q22.3. Alternatively-spliced transcript variants have been identified. [provided by RefSeq, Jan 2015]

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=0.09990442).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198693.4. 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
	KRTAP10-2	NM_198693.4	MANE Select	c.382C>A	p.Pro128Thr	missense	Exon 1 of 1	NP_941966.1	P60368-1
	TSPEAR	NM_144991.3	MANE Select	c.303+16708C>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.99+16708C>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-2	ENST00000391621.1	TSL:6 MANE Select	c.382C>A	p.Pro128Thr	missense	Exon 1 of 1	ENSP00000375479.1	P60368-1
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.303+16708C>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.258+16708C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419736 Hom.: 0 Cov.: 165 AF XY: 0.00000425 AC XY: 3 AN XY: 705550

African (AFR) AF: 0.00 AC: 0 AN: 31804

American (AMR) AF: 0.00 AC: 0 AN: 41752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24946

East Asian (EAS) AF: 0.00 AC: 0 AN: 36776

South Asian (SAS) AF: 0.0000363 AC: 3 AN: 82556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085698

Other (OTH) AF: 0.00 AC: 0 AN: 58232

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.029
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.019
Sift	Benign	0.035	D
Sift4G	Uncertain	0.060	T
Polyphen		0.44	B
Vest4		0.13
MutPred		0.27		Gain of sheet (P = 0.0477)
MVP		0.067
MPC		0.061
ClinPred		0.36	T
GERP RS		1.7
PromoterAI		-0.017	Neutral
Varity_R		0.17
gMVP		0.076
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs374542929; hg19: chr21-45970960; COSMIC: COSV59952051;