Genetic Variant NM_033045.4:c.1720G>C (chr12-52378117-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_033045.4(KRT84):c.1720G>C(p.Gly574Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000975 in 1,537,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 2 hom. )

Consequence

KRT84
NM_033045.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00

Publications

2 publications found

Variant links:

Genes affected

KRT84 (HGNC:6461): (keratin 84) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin is contained primarily in the filiform tongue papilla, among other hair keratins. [provided by RefSeq, Jul 2008]

KRT84 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016344398).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033045.4. 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
	KRT84	NM_033045.4	MANE Select	c.1720G>C	p.Gly574Arg	missense	Exon 9 of 9	NP_149034.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT84	ENST00000257951.3	TSL:1 MANE Select	c.1720G>C	p.Gly574Arg	missense	Exon 9 of 9	ENSP00000257951.3	Q9NSB2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000146

AC:

AN:

164236

AF XY:

0.000146

show subpopulations

Gnomad AFR exome

AF:

0.000391

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.0000772

AC:

107

AN:

1385696

Hom.:

Cov.:

AF XY:

0.0000789

AC XY:

AN XY:

684436

show subpopulations

African (AFR)

AF:

0.0000665

AC:

AN:

30090

American (AMR)

AF:

0.00

AC:

AN:

32584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22332

East Asian (EAS)

AF:

0.000651

AC:

AN:

35354

South Asian (SAS)

AF:

0.0000136

AC:

AN:

73642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50656

Middle Eastern (MID)

AF:

0.000205

AC:

AN:

4870

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

1079102

Other (OTH)

AF:

0.00130

AC:

AN:

57066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000282

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41556

American (AMR)

AF:

0.000980

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00271

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000712

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.000141

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

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

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.026

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.53

M_CAP

Benign

0.028

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

PhyloP100

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.034

Sift4G

Uncertain

0.032

Polyphen

0.020

Vest4

0.27

MutPred

0.18

Gain of catalytic residue at L570 (P = 0.0153)

MVP

0.68

MPC

0.030

ClinPred

0.026

GERP RS

2.9

Varity_R

0.054

gMVP

0.37

Mutation Taster

=97/3

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over