12-52314457-G-A

Position:

• chr12-52314457-G-A

Variant summary

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

The NM_002282.3(KRT83):​c.*174C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 687,802 control chromosomes in the GnomAD database, including 152,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38610 hom., cov: 34)
  • Exomes 𝑓: 0.65 (114339 hom.)
• Consequence: KRT83 NM_002282.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.372

Genes affected

KRT83 (HGNC:6460): (keratin 83) 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 KRTHB1 and KRTHB6, is found primarily in the hair cortex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-52314457-G-A is Benign according to our data. Variant chr12-52314457-G-A is described in ClinVar as [Benign]. Clinvar id is 309489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT83	NM_002282.3	c.*174C>T		3_prime_UTR_variant	9/9	ENST00000293670.3	NP_002273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT83	ENST00000293670	c.*174C>T		3_prime_UTR_variant	9/9	1	NM_002282.3	ENSP00000293670.3

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107316 AN: 152026 Hom.: 38553 Cov.: 34

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.651 AC: 348831 AN: 535658 Hom.: 114339 Cov.: 6 AF XY: 0.651 AC XY: 184836 AN XY: 283738

Gnomad4 AFR exome AF: 0.854

Gnomad4 AMR exome AF: 0.577

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.668

Gnomad4 SAS exome AF: 0.664

Gnomad4 FIN exome AF: 0.642

Gnomad4 NFE exome AF: 0.646

Gnomad4 OTH exome AF: 0.666

GnomAD4 genome AF: 0.706 AC: 107427 AN: 152144 Hom.: 38610 Cov.: 34 AF XY: 0.704 AC XY: 52396 AN XY: 74378

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.679

Alfa AF: 0.636 Hom.: 9399

Bravo AF: 0.708

Asia WGS AF: 0.712 AC: 2477 AN: 3478

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Beaded hair Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.2
DANN	Benign	0.87

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: rs2852456; hg19: chr12-52708241; COSMIC: COSV53338245;