8-22130720-A-G

Position:

• chr8-22130720-A-G

Variant summary

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

The NM_005144.5(HR):​c.-333T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 151,986 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (19 hom., cov: 34)
  • Exomes 𝑓: 0.0093 (0 hom.)
• Consequence: HR NM_005144.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.956

Genes affected

HR (HGNC:5172): (HR lysine demethylase and nuclear receptor corepressor) This gene encodes a protein that is involved in hair growth. This protein functions as a transcriptional corepressor of multiple nuclear receptors, including thyroid hormone receptor, the retinoic acid receptor-related orphan receptors and the vitamin D receptors, and it interacts with histone deacetylases. The translation of this protein is modulated by a regulatory open reading frame (ORF) that exists upstream of the primary ORF. Mutations in this upstream ORF cause Marie Unna hereditary hypotrichosis (MUHH), an autosomal dominant form of genetic hair loss. Mutations in this gene also cause autosomal recessive congenital alopecia and atrichia with papular lesions, other diseases resulting in hair loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

HRURF (HGNC:55085): (HR upstream open reading frame) Implicated in hypotrichosis 4. [provided by Alliance of Genome Resources, Apr 2022]

HR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 8-22130720-A-G is Benign according to our data. Variant chr8-22130720-A-G is described in ClinVar as [Benign]. Clinvar id is 362537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0159 (2408/151878) while in subpopulation NFE AF= 0.0205 (1391/67916). AF 95% confidence interval is 0.0196. There are 19 homozygotes in gnomad4. There are 1171 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.-333T>C		5_prime_UTR_variant	1/19	ENST00000381418.9	NP_005135.2
HRURF	NM_001394132.1	c.-12T>C		5_prime_UTR_variant	1/1	ENST00000518377.3	NP_001381061.1
HR	NM_018411.4	c.-333T>C		5_prime_UTR_variant	1/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.-333T>C		5_prime_UTR_variant	1/19	1	NM_005144.5	ENSP00000370826.4
HRURF	ENST00000518377.3	c.-12T>C		5_prime_UTR_variant	1/1	4	NM_001394132.1	ENSP00000505144.1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2409 AN: 151770 Hom.: 19 Cov.: 34

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.000974

Gnomad SAS AF: 0.00707

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.00926 AC: 1 AN: 108 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0159 AC: 2408 AN: 151878 Hom.: 19 Cov.: 34 AF XY: 0.0158 AC XY: 1171 AN XY: 74254

Gnomad4 AFR AF: 0.00676

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.000977

Gnomad4 SAS AF: 0.00707

Gnomad4 FIN AF: 0.0276

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0202 Hom.: 3

Bravo AF: 0.0148

Asia WGS AF: 0.00435 AC: 15 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrichia with papular lesions Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Alopecia universalis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
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: rs147674174; hg19: chr8-21988233; COSMIC: COSV57195123; COSMIC: COSV57195123;