Genetic Variant KRT74:p.Gly498Arg (chr12-52567067-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_175053.4(KRT74):c.1492G>A(p.Gly498Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,594,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

KRT74
NM_175053.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.325

Publications

2 publications found

Variant links:

Genes affected

KRT74 (HGNC:28929): (keratin 74) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This protein belongs to a family of keratins that are specifically expressed in the inner root sheath of hair follicles.[provided by RefSeq, Jun 2009]

KRT74 Gene-Disease associations (from GenCC):

autosomal dominant wooly hair
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypotrichosis 3
Inheritance: AD Classification: MODERATE Submitted by: G2P
hypotrichosis simplex of the scalp
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated familial wooly hair disorder
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pure hair and nail ectodermal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT74 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=0.065021515).

BS2

High AC in GnomAdExome4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175053.4. 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
	KRT74	NM_175053.4	MANE Select	c.1492G>A	p.Gly498Arg	missense	Exon 9 of 9	NP_778223.2	Q7RTS7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT74	ENST00000305620.3	TSL:1 MANE Select	c.1492G>A	p.Gly498Arg	missense	Exon 9 of 9	ENSP00000307240.2	Q7RTS7
KRT74	ENST00000549343.5	TSL:5	c.1534G>A	p.Gly512Arg	missense	Exon 10 of 10	ENSP00000447447.1	F8W1S1
KRT74	ENST00000546384.1	TSL:4	n.479G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000247

AC:

AN:

243186

AF XY:

0.0000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000591

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1442476

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

714066

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33088

American (AMR)

AF:

0.0000684

AC:

AN:

43852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25548

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39238

South Asian (SAS)

AF:

0.00

AC:

AN:

84776

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53000

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0000264

AC:

AN:

1097944

Other (OTH)

AF:

0.0000842

AC:

AN:

59374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000165

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

0.076

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.4

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.067

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.50

M_CAP

Benign

0.017

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.0

PhyloP100

-0.33

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.11

Sift

Benign

0.033

Sift4G

Uncertain

0.023

Polyphen

0.033

Vest4

0.070

MutPred

0.40

Gain of catalytic residue at G498 (P = 0.0093)

MVP

0.15

MPC

0.078

ClinPred

0.025

GERP RS

-0.70

Varity_R

0.12

gMVP

0.10

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over