Genetic Variant KRTAP5-1:p.Gly200Cys (chr11-1584652-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005922.1(KRTAP5-1):c.598G>T(p.Gly200Cys) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G200S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000093 ( 0 hom., cov: 27)

Failed GnomAD Quality Control

Consequence

KRTAP5-1
NM_001005922.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.04

Publications

0 publications found

Variant links:

Genes affected

KRTAP5-1 (HGNC:23596): (keratin associated protein 5-1) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP5-1 links:

KRTAP5-AS1 (HGNC:27877): (KRTAP5-1/KRTAP5-2 antisense RNA 1)

KRTAP5-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048812985).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005922.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP5-1	NM_001005922.1	MANE Select	c.598G>T	p.Gly200Cys	missense	Exon 1 of 1	NP_001005922.1	Q6L8H4
	KRTAP5-AS1	NR_021489.2		n.328+11584C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRTAP5-1	ENST00000382171.2	TSL:6 MANE Select	c.598G>T	p.Gly200Cys	missense	Exon 1 of 1	ENSP00000371606.2	Q6L8H4
KRTAP5-AS1	ENST00000424148.1	TSL:2	n.328+11584C>A		intron	N/A
KRTAP5-AS1	ENST00000524947.1	TSL:4	n.235-12596C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000929

AC:

AN:

107640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000344

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000929

AC:

AN:

107640

Hom.:

Cov.:

AF XY:

0.0000192

AC XY:

AN XY:

52154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000344

AC:

AN:

29038

American (AMR)

AF:

0.00

AC:

AN:

10512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2678

East Asian (EAS)

AF:

0.00

AC:

AN:

3866

South Asian (SAS)

AF:

0.00

AC:

AN:

3198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

49306

Other (OTH)

AF:

0.00

AC:

AN:

1430

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.64

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0021

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.00029

M_CAP

Benign

0.0022

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

PhyloP100

-3.0

PROVEAN

Benign

2.0

REVEL

Benign

0.049

Sift

Pathogenic

0.0

Sift4G

Benign

0.25

Polyphen

0.0040

Vest4

0.17

MutPred

0.19

Loss of glycosylation at S199 (P = 0.032)

MVP

0.067

MPC

0.043

ClinPred

0.066

GERP RS

-5.4

Varity_R

0.14

gMVP

0.018

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over