chr21-44573877-C-A

Variant names:

• chr21-44573877-C-A
• rs782039372
• NM_198687.2:c.119C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_198687.2(KRTAP10-4):​c.119C>A​(p.Pro40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,612,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 49)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.277
• Publications: 0 publications found

Genes affected

KRTAP10-4 (HGNC:20521): (keratin associated protein 10-4) This is an intronless gene located in a cluster of related genes on the q arm of chromosome 21. The proteins encoded by these genes form disulfide bonds with cysteine residues in hair keratins, thereby contributing to the structure and stability of hair fibers. [provided by RefSeq, Apr 2014]

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2156373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-4	NM_198687.2	c.119C>A	p.Pro40His	missense_variant	Exon 1 of 1	ENST00000400374.4	NP_941960.2
TSPEAR	NM_144991.3	c.83-5872G>T		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-5872G>T		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-4	ENST00000400374.4	c.119C>A	p.Pro40His	missense_variant	Exon 1 of 1	6	NM_198687.2	ENSP00000383225.3
TSPEAR	ENST00000323084.9	c.83-5872G>T		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-5872G>T		intron_variant	Intron 2 of 12			ENSP00000496535.1
TSPEAR	ENST00000397916.1	n.-61G>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151562 Hom.: 0 Cov.: 49

Gnomad AFR AF: 0.000613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245756 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461114 Hom.: 0 Cov.: 233 AF XY: 0.0000358 AC XY: 26 AN XY: 726874

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000542 AC: 18 AN: 33214

American (AMR) AF: 0.0000448 AC: 2 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5548

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111950

Other (OTH) AF: 0.0000166 AC: 1 AN: 60346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151672 Hom.: 0 Cov.: 49 AF XY: 0.000202 AC XY: 15 AN XY: 74206

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000611 AC: 25 AN: 40916

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119C>A (p.P40H) alteration is located in exon 1 (coding exon 1) of the KRTAP10-4 gene. This alteration results from a C to A substitution at nucleotide position 119, causing the proline (P) at amino acid position 40 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.96
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.089	T;.;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.28
PrimateAI	Benign	0.19	T
PROVEAN	Pathogenic	-7.5	.;D;.
REVEL	Benign	0.091
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.020	.;D;.
Vest4		0.086
MutPred		0.48		.;Loss of catalytic residue at P39 (P = 0.0488);.;
MVP		0.12
MPC		1.4
ClinPred		0.92	D
GERP RS		-1.3
PromoterAI		-0.053	Neutral
gMVP		0.071
Mutation Taster		=100/0	polymorphism

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: rs782039372; hg19: chr21-45993754;