Genetic Variant NM_031960.3:c.377G>T (chr17-41097708-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031960.3(KRTAP4-8):c.377G>T(p.Arg126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 708,280 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000046 ( 3 hom. )

Consequence

KRTAP4-8
NM_031960.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.56

Publications

7 publications found

Variant links:

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09813452).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031960.3. 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
	KRTAP4-8	NM_031960.3	MANE Select	c.377G>T	p.Arg126Leu	missense	Exon 1 of 1	NP_114166.1	Q9BYQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	ENST00000333822.5	TSL:6 MANE Select	c.377G>T	p.Arg126Leu	missense	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.0000161

AC:

AN:

124130

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:

0.0000342

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000298

AC:

AN:

100516

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000133

Gnomad NFE exome

AF:

0.0000526

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000462

AC:

AN:

584150

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

297768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15276

American (AMR)

AF:

0.00

AC:

AN:

24696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13846

East Asian (EAS)

AF:

0.00

AC:

AN:

33362

South Asian (SAS)

AF:

0.00

AC:

AN:

47000

European-Finnish (FIN)

AF:

0.0000610

AC:

AN:

32780

Middle Eastern (MID)

AF:

0.000455

AC:

AN:

2196

European-Non Finnish (NFE)

AF:

0.0000570

AC:

AN:

386010

Other (OTH)

AF:

0.0000690

AC:

AN:

28984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

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:

0.0000161

AC:

AN:

124130

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

60568

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28576

American (AMR)

AF:

0.00

AC:

AN:

13486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3026

East Asian (EAS)

AF:

0.00

AC:

AN:

4754

South Asian (SAS)

AF:

0.00

AC:

AN:

4202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

58516

Other (OTH)

AF:

0.00

AC:

AN:

1770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

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:

0.00

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

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.072

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.13

M_CAP

Benign

0.0021

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

4.0

PhyloP100

-1.6

PrimateAI

Benign

0.18

PROVEAN

Pathogenic

-4.9

REVEL

Benign

0.024

Sift

Uncertain

0.024

Sift4G

Uncertain

0.057

Polyphen

0.065

Vest4

0.14

MutPred

0.51

Loss of phosphorylation at S128 (P = 0.0545)

MVP

0.040

MPC

0.11

ClinPred

0.22

GERP RS

-2.0

PromoterAI

0.0062

Neutral

(source)

Varity_R

0.16

gMVP

0.12

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over