8-22130954-T-TAGAGCGCGGCGGAGAGCGCGGCGG

Position:

• chr8-22130954-T-TAGAGCGCGGCGGAGAGCGCGGCGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005144.5(HR):​c.-568_-567insCCGCCGCGCTCTCCGCCGCGCTCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 152,128 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HR NM_005144.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.204

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0038 (578/152128) while in subpopulation AFR AF= 0.00856 (355/41484). AF 95% confidence interval is 0.00782. There are 4 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.-568_-567insCCGCCGCGCTCTCCGCCGCGCTCT		5_prime_UTR_variant	1/19	ENST00000381418.9	NP_005135.2
HRURF	NM_001394132.1	c.-247_-246insCCGCCGCGCTCTCCGCCGCGCTCT		5_prime_UTR_variant	1/1	ENST00000518377.3	NP_001381061.1
HR	NM_018411.4	c.-568_-567insCCGCCGCGCTCTCCGCCGCGCTCT		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.-568_-567insCCGCCGCGCTCTCCGCCGCGCTCT		5_prime_UTR_variant	1/19	1	NM_005144.5	ENSP00000370826.4
HRURF	ENST00000518377.3	c.-247_-246insCCGCCGCGCTCTCCGCCGCGCTCT		5_prime_UTR_variant	1/1	4	NM_001394132.1	ENSP00000505144.1
HR	ENST00000680789.1	c.-568_-567insCCGCCGCGCTCTCCGCCGCGCTCT		5_prime_UTR_variant	2/20			ENSP00000505181.1
HR	ENST00000312841.9	c.-568_-567insCCGCCGCGCTCTCCGCCGCGCTCT		5_prime_UTR_variant	1/18	5		ENSP00000326765.8

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152012 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00858

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00382

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152128 Hom.: 4 Cov.: 34 AF XY: 0.00378 AC XY: 281 AN XY: 74388

Gnomad4 AFR AF: 0.00856

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000185 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	HR: BS2 -

Atrichia with papular lesions Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Alopecia universalis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs568964531; hg19: chr8-21988467;