12-52544537-G-A

Position:

• chr12-52544537-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000267119.6(KRT71):​c.1567C>T​(p.Arg523Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,946 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R523Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (18 hom.)
• Consequence: KRT71 ENST00000267119.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.26

Genes affected

KRT71 (HGNC:28927): (keratin 71) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene encodes a protein that is expressed in the inner root sheath of hair follicles. The type II keratins are clustered in a region of chromosome 12q13.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008432865).
• BP6: Variant 12-52544537-G-A is Benign according to our data. Variant chr12-52544537-G-A is described in ClinVar as [Benign]. Clinvar id is 778635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000654 (956/1461686) while in subpopulation AFR AF= 0.0161 (540/33476). AF 95% confidence interval is 0.015. There are 18 homozygotes in gnomad4_exome. There are 479 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 658 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT71	NM_033448.3	c.1567C>T	p.Arg523Trp	missense_variant	9/9	ENST00000267119.6	NP_258259.1
KRT71	XM_047428197.1	c.1441C>T	p.Arg481Trp	missense_variant	8/8		XP_047284153.1
KRT71	XM_017018749.2	c.1321C>T	p.Arg441Trp	missense_variant	10/10		XP_016874238.1
KRT71	XM_047428196.1	c.1030-188C>T		intron_variant			XP_047284152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT71	ENST00000267119.6	c.1567C>T	p.Arg523Trp	missense_variant	9/9	1	NM_033448.3	ENSP00000267119	P1

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 655 AN: 152142 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00118 AC: 297 AN: 251404 Hom.: 1 AF XY: 0.00106 AC XY: 144 AN XY: 135866

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000654 AC: 956 AN: 1461686 Hom.: 18 Cov.: 30 AF XY: 0.000659 AC XY: 479 AN XY: 727156

Gnomad4 AFR exome AF: 0.0161

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152260 Hom.: 5 Cov.: 32 AF XY: 0.00414 AC XY: 308 AN XY: 74450

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00495

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00134 AC: 163

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

KRT71-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 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	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.54	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.83
MPC		0.49
ClinPred		0.055	T
GERP RS		3.5
Varity_R		0.25
gMVP		0.60

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: rs144494659; hg19: chr12-52938321;