12-52544728-G-C

Position:

• chr12-52544728-G-C

Variant summary

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

The NM_033448.3(KRT71):​c.1376C>G​(p.Thr459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,612,102 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (23 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (14 hom.)
• Consequence: KRT71 NM_033448.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54

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=0.003920436).
• BP6: Variant 12-52544728-G-C is Benign according to our data. Variant chr12-52544728-G-C is described in ClinVar as [Benign]. Clinvar id is 714538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (1141/152312) while in subpopulation AFR AF= 0.0254 (1057/41564). AF 95% confidence interval is 0.0242. There are 23 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT71	NM_033448.3	c.1376C>G	p.Thr459Ser	missense_variant	9/9	ENST00000267119.6	NP_258259.1
KRT71	XM_047428197.1	c.1250C>G	p.Thr417Ser	missense_variant	8/8		XP_047284153.1
KRT71	XM_017018749.2	c.1130C>G	p.Thr377Ser	missense_variant	10/10		XP_016874238.1
KRT71	XM_047428196.1	c.1030-379C>G		intron_variant			XP_047284152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT71	ENST00000267119.6	c.1376C>G	p.Thr459Ser	missense_variant	9/9	1	NM_033448.3	ENSP00000267119.5

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1119 AN: 152194 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00176 AC: 433 AN: 246114 Hom.: 5 AF XY: 0.00135 AC XY: 180 AN XY: 133550

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000253

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000823 AC: 1202 AN: 1459790 Hom.: 14 Cov.: 42 AF XY: 0.000697 AC XY: 506 AN XY: 726268

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00749 AC: 1141 AN: 152312 Hom.: 23 Cov.: 33 AF XY: 0.00752 AC XY: 560 AN XY: 74468

Gnomad4 AFR AF: 0.0254

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000646 Hom.: 1

Bravo AF: 0.00790

ESP6500AA AF: 0.0194 AC: 84

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.00209 AC: 253

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.039	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.20
Sift	Benign	0.69	T
Sift4G	Benign	0.86	T
Polyphen		0.0020	B
Vest4		0.21
MutPred		0.34		Gain of catalytic residue at S460 (P = 0);
MVP		0.75
MPC		0.081
ClinPred		0.033	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs112987888; hg19: chr12-52938512;