8-22114448-T-TA

Position:

• chr8-22114448-T-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005144.5(HR):​c.*1251_*1252insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,590 control chromosomes in the GnomAD database, including 1,882 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1881 hom., cov: 30)
  • Exomes 𝑓: 0.083 (1 hom.)
• Consequence: HR NM_005144.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.97

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 8-22114448-T-TA is Benign according to our data. Variant chr8-22114448-T-TA is described in ClinVar as [Benign]. Clinvar id is 362455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.*1251_*1252insT		3_prime_UTR_variant	19/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.*1251_*1252insT		3_prime_UTR_variant	18/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.*1251_*1252insT		3_prime_UTR_variant	19/19	1	NM_005144.5	ENSP00000370826	P1
HR	ENST00000312841.9	c.*1251_*1252insT		3_prime_UTR_variant	18/18	5		ENSP00000326765
HR	ENST00000680789.1	c.*1251_*1252insT		3_prime_UTR_variant	20/20			ENSP00000505181	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21936 AN: 152050 Hom.: 1874 Cov.: 30

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.0829 AC: 35 AN: 422 Hom.: 1 Cov.: 0 AF XY: 0.0720 AC XY: 18 AN XY: 250

Gnomad4 FIN exome AF: 0.0845

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.144 AC: 21960 AN: 152168 Hom.: 1881 Cov.: 30 AF XY: 0.137 AC XY: 10203 AN XY: 74404

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.00770

Gnomad4 SAS AF: 0.0405

Gnomad4 FIN AF: 0.0840

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.145

Bravo AF: 0.153

Asia WGS AF: 0.0380 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Atrichia with papular lesions Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Alopecia universalis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs11446222; hg19: chr8-21971961;