12-52286265-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002281.4(KRT81):c.1508G>A(p.Arg503Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,554,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.373

Genes affected

KRT81 (HGNC:6458): (keratin 81) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin, as well as KRTHB3 and KRTHB6, is found primarily in the hair cortex. Mutations in this gene and KRTHB6 have been observed in patients with a rare dominant hair disease, monilethrix. Some human genome assemblies (example T2T-CHM13) have a non-coding version of the gene due to the presence of a SNP that introduces a premature stop codon after codon 281. [provided by RefSeq, Jan 2024]

KRT86 (HGNC:6463): (keratin 86) This gene encodes a type II keratin protein, which heterodimerizes with type I keratins to form hair and nails. This gene is present in a cluster of related genes and pseudogenes on chromosome 12. Mutations in this gene have been observed in patients with the hair disease monilethrix. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05891472).
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT81	NM_002281.4	c.1508G>A	p.Arg503Gln	missense_variant	9/9	ENST00000327741.9
KRT86	NM_001320198.2	c.-5+10319C>T		intron_variant		ENST00000423955.7
KRT81	XM_047428838.1	c.1508G>A	p.Arg503Gln	missense_variant	10/10
KRT86	XM_005268866.5	c.129+10319C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT81	ENST00000327741.9	c.1508G>A	p.Arg503Gln	missense_variant	9/9	1	NM_002281.4	P1
KRT86	ENST00000423955.7	c.-5+10319C>T		intron_variant		2	NM_001320198.2	P1
KRT86	ENST00000553310.6	c.-4-15648C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000207 AC: 32 AN: 154228 Hom.: 0 AF XY: 0.000172 AC XY: 14 AN XY: 81588

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00101

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000190 AC: 267 AN: 1401718 Hom.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 111 AN XY: 691618

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.000250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000358

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000464 AC: 2

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000830 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.1508G>A (p.R503Q) alteration is located in exon 9 (coding exon 9) of the KRT81 gene. This alteration results from a G to A substitution at nucleotide position 1508, causing the arginine (R) at amino acid position 503 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.044	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.24
Sift	Benign	0.055	T;.
Sift4G	Benign	0.069	T;T
Polyphen		0.99	D;.
Vest4		0.20
MVP		0.69
MPC		0.43
ClinPred		0.077	T
GERP RS		4.4
Varity_R		0.075
gMVP		0.044

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: rs138935547; hg19: chr12-52680049; COSMIC: COSV59808972;