12-52430579-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_004693.3(KRT75):c.997C>T(p.Arg333Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,614,112 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (5 hom.)
• Consequence: KRT75 NM_004693.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.05

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.078255296).
• BP6: Variant 12-52430579-G-A is Benign according to our data. Variant chr12-52430579-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3049320.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 277 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT75	NM_004693.3	c.997C>T	p.Arg333Cys	missense_variant	5/9	ENST00000252245.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT75	ENST00000252245.6	c.997C>T	p.Arg333Cys	missense_variant	5/9	1	NM_004693.3	P1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152140 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00191 AC: 481 AN: 251496 Hom.: 3 AF XY: 0.00177 AC XY: 240 AN XY: 135922

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00294 AC: 4304 AN: 1461854 Hom.: 5 Cov.: 35 AF XY: 0.00282 AC XY: 2049 AN XY: 727230

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152258 Hom.: 1 Cov.: 33 AF XY: 0.00163 AC XY: 121 AN XY: 74448

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00212

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KRT75-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2022

This variant is classified as likely 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	0.22
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.078	T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.76
MVP		0.80
MPC		0.54
ClinPred		0.073	T
GERP RS		4.8
Varity_R		0.31
gMVP		0.57

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: rs2232396; hg19: chr12-52824363; COSMIC: COSV52875413; COSMIC: COSV52875413;