12-52424593-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004693.3(KRT75):c.1580G>A(p.Arg527Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,980 control chromosomes in the GnomAD database, including 22,905 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2126 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20779 hom.)
• Consequence: KRT75 NM_004693.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.61

Genes affected

KRT75 (HGNC:24431): (keratin 75) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. This gene is expressed in the companion layer, upper germinative matrix region of the hair follicle, and medulla of the hair shaft. The encoded protein plays an essential role in hair and nail formation. Variations in this gene have been associated with the hair disorders pseudofolliculitis barbae (PFB) and loose anagen hair syndrome (LAHS). [provided by RefSeq, Oct 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017234087).
• BP6: Variant 12-52424593-C-T is Benign according to our data. Variant chr12-52424593-C-T is described in ClinVar as [Benign]. Clinvar id is 3059432.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT75	NM_004693.3	c.1580G>A	p.Arg527Gln	missense_variant	9/9	ENST00000252245.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT75	ENST00000252245.6	c.1580G>A	p.Arg527Gln	missense_variant	9/9	1	NM_004693.3	P1
	ENST00000548135.1	n.292-3564C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24147 AN: 152028 Hom.: 2118 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.178 AC: 44689 AN: 251384 Hom.: 4261 AF XY: 0.175 AC XY: 23761 AN XY: 135884

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.155

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.166 AC: 242193 AN: 1461836 Hom.: 20779 Cov.: 32 AF XY: 0.166 AC XY: 120447 AN XY: 727226

Gnomad4 AFR exome AF: 0.0949

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.159 AC: 24160 AN: 152144 Hom.: 2126 Cov.: 32 AF XY: 0.163 AC XY: 12158 AN XY: 74370

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.160

Alfa AF: 0.154 Hom.: 3054

Bravo AF: 0.156

TwinsUK AF: 0.160 AC: 592

ALSPAC AF: 0.160 AC: 615

ESP6500AA AF: 0.112 AC: 495

ESP6500EA AF: 0.163 AC: 1401

ExAC AF: 0.170 AC: 20580

Asia WGS AF: 0.192 AC: 665 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.149

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KRT75-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.26	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Benign	0.045	D
Sift4G	Benign	0.38	T
Polyphen		1.0	D
Vest4		0.34
MPC		0.10
ClinPred		0.018	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs61730614; hg19: chr12-52818377; COSMIC: COSV52871614; COSMIC: COSV52871614;