rs2232387

Positions:

• chr12-52433824-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BA1

The NM_004693.3(KRT75):​c.481G>A​(p.Ala161Thr) variant causes a missense change. The variant allele was found at a frequency of 0.114 in 1,613,898 control chromosomes in the GnomAD database, including 11,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1633 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9627 hom.)
• Consequence: KRT75 NM_004693.3 missense
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:2
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026835501).
• BP6: Variant 12-52433824-C-T is Benign according to our data. Variant chr12-52433824-C-T is described in ClinVar as [Benign, risk_factor]. Clinvar id is 1891.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT75	NM_004693.3	c.481G>A	p.Ala161Thr	missense_variant	1/9	ENST00000252245.6	NP_004684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT75	ENST00000252245.6	c.481G>A	p.Ala161Thr	missense_variant	1/9	1	NM_004693.3	ENSP00000252245.5

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21155 AN: 151964 Hom.: 1629 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0718

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.125 AC: 31496 AN: 251484 Hom.: 2275 AF XY: 0.124 AC XY: 16803 AN XY: 135918

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0684

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.111 AC: 162095 AN: 1461816 Hom.: 9627 Cov.: 73 AF XY: 0.111 AC XY: 81044 AN XY: 727220

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.0717

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.139 AC: 21180 AN: 152082 Hom.: 1633 Cov.: 32 AF XY: 0.140 AC XY: 10372 AN XY: 74346

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.0718

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.154

Alfa AF: 0.119 Hom.: 2427

Bravo AF: 0.146

TwinsUK AF: 0.0976 AC: 362

ALSPAC AF: 0.108 AC: 416

ESP6500AA AF: 0.179 AC: 789

ESP6500EA AF: 0.111 AC: 958

ExAC AF: 0.123 AC: 14943

Asia WGS AF: 0.111 AC: 390 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.120

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

KRT75-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 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). -

Pseudofolliculitis barbae Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.29
MPC		0.47
ClinPred		0.10	T
GERP RS		5.7
Varity_R		0.85
gMVP		0.86

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: rs2232387; hg19: chr12-52827608; COSMIC: COSV52872728;