Genetic Variant NM_001386841.1:c.226C>T (chr17-41184629-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386841.1(KRTAP4-1):c.226C>T(p.Pro76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,595,114 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P76A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 21)

Exomes 𝑓: 0.0000048 ( 1 hom. )

Consequence

KRTAP4-1
NM_001386841.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Publications

0 publications found

Variant links:

Genes affected

KRTAP4-1 (HGNC:18907): (keratin associated protein 4-1) 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]

KRTAP4-1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2018528).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386841.1. 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
	KRTAP4-1	NM_001386841.1	MANE Select	c.226C>T	p.Pro76Ser	missense	Exon 1 of 1	NP_001373770.1	Q9BYQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-1	ENST00000398472.2	TSL:6 MANE Select	c.226C>T	p.Pro76Ser	missense	Exon 1 of 1	ENSP00000381489.1	Q9BYQ7

Frequencies

GnomAD3 genomes

AF:

0.00000679

AC:

AN:

147340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

1447774

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.00

AC:

AN:

43800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

38976

South Asian (SAS)

AF:

0.00

AC:

AN:

84112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52774

Middle Eastern (MID)

AF:

0.000390

AC:

AN:

5128

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104482

Other (OTH)

AF:

0.0000503

AC:

AN:

59680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00000679

AC:

AN:

147340

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71564

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39594

American (AMR)

AF:

0.00

AC:

AN:

14670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

4966

South Asian (SAS)

AF:

0.00

AC:

AN:

4456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67004

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000843

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.64

M_CAP

Benign

0.0066

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.93

PhyloP100

1.5

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-6.6

REVEL

Benign

0.089

Sift

Uncertain

0.0070

Sift4G

Benign

0.13

Polyphen

0.079

Vest4

0.21

MutPred

0.51

Gain of sheet (P = 0.0166)

MVP

0.14

MPC

0.18

ClinPred

0.31

GERP RS

0.14

PromoterAI

-0.0069

Neutral

(source)

Varity_R

0.21

gMVP

0.057

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over