NM_033448.3:c.1568G>A

Variant names:

• chr12-52544536-C-T
• rs2292506
• NM_033448.3:c.1568G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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. R523W) has been classified as Likely benign.

• 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
• Publications: 19 publications found

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]

KRT71 Gene-Disease associations (from GenCC):

• isolated familial wooly hair disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypotrichosis 13

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033448.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT71	NM_033448.3	MANE Select	c.1568G>A	p.Arg523Gln	missense	Exon 9 of 9	NP_258259.1	Q3SY84

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT71	ENST00000267119.6	TSL:1 MANE Select	c.1568G>A	p.Arg523Gln	missense	Exon 9 of 9	ENSP00000267119.5	Q3SY84

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

GnomAD2 exomes AF: 0.117 AC: 29528 AN: 251392 AF XY: 0.113

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 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

African (AFR) AF: 0.210 AC: 7041 AN: 33462

American (AMR) AF: 0.193 AC: 8633 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 1384 AN: 26120

East Asian (EAS) AF: 0.205 AC: 8133 AN: 39700

South Asian (SAS) AF: 0.169 AC: 14569 AN: 86250

European-Finnish (FIN) AF: 0.110 AC: 5895 AN: 53390

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5764

European-Non Finnish (NFE) AF: 0.0602 AC: 66969 AN: 1111744

Other (OTH) AF: 0.0860 AC: 5191 AN: 60386

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

African (AFR) AF: 0.209 AC: 8654 AN: 41450

American (AMR) AF: 0.165 AC: 2518 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0479 AC: 166 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1111 AN: 5164

South Asian (SAS) AF: 0.180 AC: 866 AN: 4810

European-Finnish (FIN) AF: 0.117 AC: 1235 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0592 AC: 4021 AN: 67976

Other (OTH) AF: 0.114 AC: 240 AN: 2114

Alfa AF: 0.0801 Hom.: 3208

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.5
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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