21-44558145-G-T

Position:

• chr21-44558145-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198696.3(KRTAP10-3):​c.571C>A​(p.Pro191Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,613,390 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: KRTAP10-3 NM_198696.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

KRTAP10-3 (HGNC:22968): (keratin associated protein 10-3) This gene encodes a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This gene encodes a member of the high sulfur KAP family. It is localized to a cluster of intronless KAPs at 21q22.3 which are located within the introns of the C21orf29 gene. [provided by RefSeq, Jul 2008]

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018901676).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-3	NM_198696.3	c.571C>A	p.Pro191Thr	missense_variant	1/1	ENST00000391620.2	NP_941969.2
TSPEAR	NM_144991.3	c.303+9640C>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.99+9640C>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-3	ENST00000391620.2	c.571C>A	p.Pro191Thr	missense_variant	1/1	6	NM_198696.3	ENSP00000375478.1
TSPEAR	ENST00000323084.9	c.303+9640C>A		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.258+9640C>A		intron_variant		1
TSPEAR	ENST00000642437.1	n.*248+9640C>A		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000514 AC: 128 AN: 248960 Hom.: 2 AF XY: 0.000667 AC XY: 90 AN XY: 134942

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000346 AC: 506 AN: 1461124 Hom.: 4 Cov.: 29 AF XY: 0.000426 AC XY: 310 AN XY: 726908

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000338 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000577 AC: 70

EpiCase AF: 0.000545

EpiControl AF: 0.000711

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

Dec 02, 2021

The c.571C>A (p.P191T) alteration is located in exon 1 (coding exon 1) of the KRTAP10-3 gene. This alteration results from a C to A substitution at nucleotide position 571, causing the proline (P) at amino acid position 191 to be replaced by a threonine (T). 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	0.086
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.099
Sift	Uncertain	0.025	D
Sift4G	Benign	0.076	T
Polyphen		0.54	P
Vest4		0.27
MVP		0.23
MPC		0.027
ClinPred		0.038	T
GERP RS		2.8
Varity_R		0.20
gMVP		0.085

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

Publications

LitVar

Other links and lift over

dbSNP: rs201268694; hg19: chr21-45978028;