12-52428680-T-C

Position:

• chr12-52428680-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004693.3(KRT75):​c.1099A>G​(p.Ile367Val) variant causes a missense change. The variant allele was found at a frequency of 0.00466 in 1,614,168 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.024 (137 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (142 hom.)
• Consequence: KRT75 NM_004693.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073229373).
• BP6: Variant 12-52428680-T-C is Benign according to our data. Variant chr12-52428680-T-C is described in ClinVar as [Benign]. Clinvar id is 788884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT75	NM_004693.3	c.1099A>G	p.Ile367Val	missense_variant	6/9	ENST00000252245.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT75	ENST00000252245.6	c.1099A>G	p.Ile367Val	missense_variant	6/9	1	NM_004693.3	P1

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3649 AN: 152158 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.00656 AC: 1649 AN: 251486 Hom.: 58 AF XY: 0.00461 AC XY: 626 AN XY: 135922

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00265 AC: 3868 AN: 1461892 Hom.: 142 Cov.: 34 AF XY: 0.00226 AC XY: 1647 AN XY: 727246

Gnomad4 AFR exome AF: 0.0899

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.0240 AC: 3661 AN: 152276 Hom.: 137 Cov.: 33 AF XY: 0.0232 AC XY: 1724 AN XY: 74452

Gnomad4 AFR AF: 0.0829

Gnomad4 AMR AF: 0.00986

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.00254 Hom.: 19

Bravo AF: 0.0278

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0847 AC: 373

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00778 AC: 945

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRT75-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0073	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.86
MPC		0.40
ClinPred		0.020	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.51

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: rs2232402; hg19: chr12-52822464;