rs750832509

chr8-22117025-C-CCCGG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005144.5(HR):c.3227_3228insCCGG(p.Ala1077ArgfsTer69) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,355,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G1076G) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: HR NM_005144.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.410

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HR	NM_005144.5	c.3227_3228insCCGG	p.Ala1077ArgfsTer69	frameshift_variant	17/19	ENST00000381418.9
HR	NM_018411.4	c.3214-598_3214-597insCCGG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HR	ENST00000381418.9	c.3227_3228insCCGG	p.Ala1077ArgfsTer69	frameshift_variant	17/19	1	NM_005144.5	P1
HR	ENST00000680789.1	c.3227_3228insCCGG	p.Ala1077ArgfsTer69	frameshift_variant	18/20			P1
HR	ENST00000312841.9	c.3214-598_3214-597insCCGG		intron_variant		5
HR	ENST00000522016.1	n.1420_1421insCCGG		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000910 AC: 1 AN: 109850 Hom.: 0 AF XY: 0.0000167 AC XY: 1 AN XY: 60060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000307

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355380 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 665540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000329

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

HR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The HR c.3224_3227dupCCGG (p.Ala1077ArgfsTer69) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ala1077ArgfsTer69 variant has been reported in a single study in which it was found in a homozygous state in two affected siblings with alopecia universalis and complete atrichia (Nucara et al. 2011). The variant was also found in a heterozygous state in the unaffected parents and an unaffected sibling. Control data are unavailable for this variant, which is not reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The variant is in a region of low sequence coverage in both the Exome Sequencing Project and the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the supporting evidence, the p.Ala1077ArgfsTer69 variant is classified as a variant of unknown significance but suspicious for pathogenicity for HR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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: rs750832509; hg19: chr8-21974538;