Genetic Variant NM_006771.4:c.1364G>A (chr17-41437419-C-T) – 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_006771.4(KRT38):c.1364G>A(p.Arg455Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,564,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KRT38
NM_006771.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.114

Publications

0 publications found

Variant links:

Genes affected

KRT38 (HGNC:6456): (keratin 38) The protein encoded by this gene is a member of the keratin gene family. As a type I hair keratin, it is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

KRT38 links:

ENSG00000234859 (HGNC:):

ENSG00000234859 links:

Genome browser will be placed here

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=0.026663512).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006771.4. 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
	KRT38	NM_006771.4	MANE Select	c.1364G>A	p.Arg455Gln	missense	Exon 7 of 7	NP_006762.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT38	ENST00000246646.4	TSL:1 MANE Select	c.1364G>A	p.Arg455Gln	missense	Exon 7 of 7	ENSP00000246646.3	O76015
ENSG00000234859	ENST00000731569.1		n.134-6505C>T		intron	N/A
ENSG00000234859	ENST00000731574.1		n.718-10415C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000478

GnomAD2 exomes

AF:

0.0000345

AC:

AN:

203040

AF XY:

0.0000269

show subpopulations

Gnomad AFR exome

AF:

0.000161

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000496

Gnomad NFE exome

AF:

0.0000210

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000113

AC:

AN:

1411920

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

701134

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

29580

American (AMR)

AF:

0.0000877

AC:

AN:

34198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24292

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35710

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80242

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5332

European-Non Finnish (NFE)

AF:

0.00000550

AC:

AN:

1091794

Other (OTH)

AF:

0.0000172

AC:

AN:

58052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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

AF:

0.0000525

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41592

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000569

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000330

AC:

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

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.042

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.49

M_CAP

Benign

0.015

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

PhyloP100

0.11

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.56

REVEL

Benign

0.18

Sift

Benign

0.34

Sift4G

Benign

0.092

Polyphen

0.0080

Vest4

0.099

MutPred

0.19

Loss of methylation at R455 (P = 0.0233)

MVP

0.38

MPC

0.044

ClinPred

0.014

GERP RS

-0.99

Varity_R

0.040

gMVP

0.12

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over