chr21-44574359-A-T

Position:

• chr21-44574359-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198687.2(KRTAP10-4):​c.601A>T​(p.Ile201Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.659

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042158037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-4	NM_198687.2	c.601A>T	p.Ile201Phe	missense_variant	1/1	ENST00000400374.4	NP_941960.2
TSPEAR	NM_144991.3	c.83-6354T>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-6354T>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-4	ENST00000400374.4	c.601A>T	p.Ile201Phe	missense_variant	1/1		NM_198687.2	ENSP00000383225	P1
TSPEAR	ENST00000323084.9	c.83-6354T>A		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000642437.1	c.*28-6354T>A		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459760 Hom.: 0 Cov.: 198 AF XY: 0.00000413 AC XY: 3 AN XY: 726208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 03, 2022

The c.601A>T (p.I201F) alteration is located in exon 1 (coding exon 1) of the KRTAP10-4 gene. This alteration results from a A to T substitution at nucleotide position 601, causing the isoleucine (I) at amino acid position 201 to be replaced by a phenylalanine (F). 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	0.095
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.76
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.0028	T;.
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.35	.;N
REVEL	Benign	0.046
Sift	Benign	0.23	.;T
Sift4G	Benign	0.69	.;T
Vest4		0.075
MutPred		0.22		.;Loss of sheet (P = 0.1158);
MVP		0.030
MPC		0.72
ClinPred		0.090	T
GERP RS		2.0
gMVP		0.022

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: chr21-45994236;