8-22131002-A-C

Position:

• chr8-22131002-A-C

Variant summary

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

The NM_005144.5(HR):​c.-615T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,186 control chromosomes in the GnomAD database, including 32,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32470 hom., cov: 35)
  • Exomes 𝑓: 0.59 (16 hom.)
• Consequence: HR NM_005144.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.213

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 8-22131002-A-C is Benign according to our data. Variant chr8-22131002-A-C is described in ClinVar as [Benign]. Clinvar id is 362542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.-615T>G		5_prime_UTR_variant	1/19	ENST00000381418.9	NP_005135.2
HRURF	NM_001394132.1	c.-294T>G		5_prime_UTR_variant	1/1	ENST00000518377.3	NP_001381061.1
HR	NM_018411.4	c.-615T>G		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.-615T>G		5_prime_UTR_variant	1/19	1	NM_005144.5	ENSP00000370826.4
HRURF	ENST00000518377.3	c.-294T>G		5_prime_UTR_variant	1/1	4	NM_001394132.1	ENSP00000505144.1
HR	ENST00000680789.1	c.-615T>G		5_prime_UTR_variant	2/20			ENSP00000505181.1
HR	ENST00000312841.9	c.-615T>G		5_prime_UTR_variant	1/18	5		ENSP00000326765.8

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98276 AN: 151980 Hom.: 32419 Cov.: 35

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.615

GnomAD4 exome AF: 0.587 AC: 54 AN: 92 Hom.: 16 Cov.: 0 AF XY: 0.575 AC XY: 46 AN XY: 80

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.566

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.647 AC: 98385 AN: 152094 Hom.: 32470 Cov.: 35 AF XY: 0.645 AC XY: 47941 AN XY: 74366

Gnomad4 AFR AF: 0.768

Gnomad4 AMR AF: 0.547

Gnomad4 ASJ AF: 0.647

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.655

Gnomad4 FIN AF: 0.619

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.616

Alfa AF: 0.633 Hom.: 16009

Bravo AF: 0.643

Asia WGS AF: 0.526 AC: 1831 AN: 3476

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 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. -

Alopecia universalis congenita 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. -

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	20
DANN	Benign	0.92

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: rs6557841; hg19: chr8-21988515; COSMIC: COSV57192037; COSMIC: COSV57192037;