21-44539373-C-G

Position:

• chr21-44539373-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_198691.3(KRTAP10-1):​c.778G>C​(p.Ala260Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,612,844 control chromosomes in the GnomAD database, including 112 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0093 (7 hom., cov: 33)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: KRTAP10-1 NM_198691.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.365

Genes affected

KRTAP10-1 (HGNC:22966): (keratin associated protein 10-1) 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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00256598).
• BP6: Variant 21-44539373-C-G is Benign according to our data. Variant chr21-44539373-C-G is described in ClinVar as [Benign]. Clinvar id is 2652759.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-1	NM_198691.3	c.778G>C	p.Ala260Pro	missense_variant	1/1	ENST00000400375.1	NP_941964.2
TSPEAR	NM_144991.3	c.304-5450G>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.100-5450G>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-1	ENST00000400375.1	c.778G>C	p.Ala260Pro	missense_variant	1/1		NM_198691.3	ENSP00000383226	P1
TSPEAR	ENST00000323084.9	c.304-5450G>C		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000397916.1	n.259-5450G>C		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*249-5450G>C		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1414 AN: 151752 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00839

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00313

Gnomad FIN AF: 0.00605

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00986 AC: 2452 AN: 248738 Hom.: 18 AF XY: 0.0101 AC XY: 1364 AN XY: 134888

Gnomad AFR exome AF: 0.00447

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000555

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.00514

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0108 AC: 15716 AN: 1460974 Hom.: 105 Cov.: 126 AF XY: 0.0107 AC XY: 7786 AN XY: 726844

Gnomad4 AFR exome AF: 0.00383

Gnomad4 AMR exome AF: 0.00716

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.000454

Gnomad4 SAS exome AF: 0.00455

Gnomad4 FIN exome AF: 0.00633

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00991

GnomAD4 genome AF: 0.00929 AC: 1411 AN: 151870 Hom.: 7 Cov.: 33 AF XY: 0.00865 AC XY: 642 AN XY: 74226

Gnomad4 AFR AF: 0.00567

Gnomad4 AMR AF: 0.00838

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00313

Gnomad4 FIN AF: 0.00605

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00997

Alfa AF: 0.00720 Hom.: 2

Bravo AF: 0.00928

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0136 AC: 117

ExAC AF: 0.0102 AC: 1237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

KRTAP10-1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.55
DANN	Benign	0.62
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.8	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	5.2	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.099
MPC		0.20
ClinPred		0.0039	T
GERP RS		-2.0
Varity_R		0.051
gMVP		0.018

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: rs143105755; hg19: chr21-45959256;