21-44539600-C-T

Position:

chr21-44539600-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_198691.3(KRTAP10-1):c.551G>A(p.Cys184Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

KRTAP10-1
NM_198691.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0780

Variant links:

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]

KRTAP10-1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012121767).

BP6

Variant 21-44539600-C-T is Benign according to our data. Variant chr21-44539600-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2381616.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KRTAP10-1	NM_198691.3 linkuse as main transcript	c.551G>A	p.Cys184Tyr	missense_variant	1/1	ENST00000400375.1	NP_941964.2
TSPEAR	NM_144991.3 linkuse as main transcript	c.304-5677G>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 linkuse as main transcript	c.100-5677G>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-1	ENST00000400375.1 linkuse as main transcript	c.551G>A	p.Cys184Tyr	missense_variant	1/1		NM_198691.3	ENSP00000383226	P1
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.304-5677G>A		intron_variant		1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.259-5677G>A		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*249-5677G>A		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251256

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461478

Hom.:

Cov.:

174

AF XY:

0.0000536

AC XY:

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000368

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000673

Hom.:

Bravo

AF:

0.000642

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.036

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.30

M_CAP

Benign

0.0036

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.085

Sift

Benign

0.087

Sift4G

Uncertain

0.051

Polyphen

0.0

Vest4

0.12

MVP

0.23

MPC

0.26

ClinPred

0.041

GERP RS

-1.4

Varity_R

0.14

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over