chr21-44574093-C-A

Position:

• chr21-44574093-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198687.2(KRTAP10-4):​c.335C>A​(p.Pro112His) 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 36)
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22933978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-4	NM_198687.2	c.335C>A	p.Pro112His	missense_variant	1/1	ENST00000400374.4
TSPEAR	NM_144991.3	c.83-6088G>T		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.-122-6088G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-4	ENST00000400374.4	c.335C>A	p.Pro112His	missense_variant	1/1		NM_198687.2	P1
TSPEAR	ENST00000323084.9	c.83-6088G>T		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*28-6088G>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 176

GnomAD4 genome Cov.: 36

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.335C>A (p.P112H) 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 335, causing the proline (P) at amino acid position 112 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	0.24
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.84
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.93	D;.
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.25	T
Vest4		0.24
MutPred		0.44		.;Gain of sheet (P = 0.0125);
MVP		0.17
MPC		0.52
ClinPred		0.51	D
GERP RS		3.0
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45993970;