12-52544536-C-T

Position:

• chr12-52544536-C-T

Variant summary

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

The NM_033448.3(KRT71):​c.1568G>A​(p.Arg523Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 1,613,626 control chromosomes in the GnomAD database, including 8,294 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1573 hom., cov: 32)
  • Exomes 𝑓: 0.081 (6721 hom.)
• Consequence: KRT71 NM_033448.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.54

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=0.0016748309).
• BP6: Variant 12-52544536-C-T is Benign according to our data. Variant chr12-52544536-C-T is described in ClinVar as [Benign]. Clinvar id is 1244815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT71	NM_033448.3	c.1568G>A	p.Arg523Gln	missense_variant	9/9	ENST00000267119.6	NP_258259.1
KRT71	XM_047428197.1	c.1442G>A	p.Arg481Gln	missense_variant	8/8		XP_047284153.1
KRT71	XM_017018749.2	c.1322G>A	p.Arg441Gln	missense_variant	10/10		XP_016874238.1
KRT71	XM_047428196.1	c.1030-187G>A		intron_variant			XP_047284152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT71	ENST00000267119.6	c.1568G>A	p.Arg523Gln	missense_variant	9/9	1	NM_033448.3	ENSP00000267119	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18894 AN: 151968 Hom.: 1564 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0479

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.117 AC: 29528 AN: 251392 Hom.: 2352 AF XY: 0.113 AC XY: 15343 AN XY: 135866

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0523

Gnomad EAS exome AF: 0.219

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0911

GnomAD4 exome AF: 0.0807 AC: 118001 AN: 1461540 Hom.: 6721 Cov.: 30 AF XY: 0.0819 AC XY: 59527 AN XY: 727112

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.0530

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0602

Gnomad4 OTH exome AF: 0.0860

GnomAD4 genome AF: 0.124 AC: 18917 AN: 152086 Hom.: 1573 Cov.: 32 AF XY: 0.129 AC XY: 9581 AN XY: 74348

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.0479

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0592

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0736 Hom.: 1465

Bravo AF: 0.132

TwinsUK AF: 0.0626 AC: 232

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.195 AC: 858

ESP6500EA AF: 0.0610 AC: 525

ExAC AF: 0.115 AC: 13953

Asia WGS AF: 0.213 AC: 741 AN: 3476

EpiCase AF: 0.0534

EpiControl AF: 0.0519

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.49	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Benign	0.068	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.095
MPC		0.52
ClinPred		0.052	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.55

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: rs2292506; hg19: chr12-52938320; COSMIC: COSV57290362;