Genetic Variant NM_033062.4:c.254G>A (chr17-41177911-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033062.4(KRTAP4-2):c.254G>A(p.Cys85Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C85S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

KRTAP4-2
NM_033062.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.95

Publications

0 publications found

Variant links:

Genes affected

KRTAP4-2 (HGNC:18900): (keratin associated protein 4-2) This protein is 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 protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

KRTAP4-2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033062.4. 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
	KRTAP4-2	NM_033062.4	MANE Select	c.254G>A	p.Cys85Tyr	missense	Exon 1 of 1	NP_149051.2	Q9BYR5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-2	ENST00000377726.3	TSL:6 MANE Select	c.254G>A	p.Cys85Tyr	missense	Exon 1 of 1	ENSP00000366955.2	Q9BYR5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432912

Hom.:

Cov.:

180

AF XY:

0.00000140

AC XY:

AN XY:

712760

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32020

American (AMR)

AF:

0.00

AC:

AN:

41434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25184

East Asian (EAS)

AF:

0.00

AC:

AN:

37440

South Asian (SAS)

AF:

0.00

AC:

AN:

83680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1096270

Other (OTH)

AF:

0.00

AC:

AN:

58608

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.66

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

4.0

PhyloP100

1.9

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-10

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.22

MutPred

0.76

Gain of sheet (P = 0.1208)

MVP

0.62

MPC

0.64

ClinPred

1.0

GERP RS

3.3

PromoterAI

0.0035

Neutral

(source)

Varity_R

0.88

gMVP

0.16

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over