Variant rs750832509 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_005144.5(HR):c.3224_3227dupCCGG(p.Ala1077fs) 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 (★). 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.410

Variant links:

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]

HR links:

HR (HGNC:):

HR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
HR	NM_005144.5 linkuse as main transcript	c.3224_3227dupCCGG	p.Ala1077fs	frameshift_variant	17/19	ENST00000381418.9	NP_005135.2	O43593-1
HR	NM_018411.4 linkuse as main transcript	c.3214-601_3214-598dupCCGG		intron_variant			NP_060881.2	O43593-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HR	ENST00000381418.9 linkuse as main transcript	c.3224_3227dupCCGG	p.Ala1077fs	frameshift_variant	17/19	1	NM_005144.5	ENSP00000370826.4	O43593-1
HR	ENST00000680789.1 linkuse as main transcript	c.3224_3227dupCCGG	p.Ala1077fs	frameshift_variant	18/20			ENSP00000505181.1	O43593-1
HR	ENST00000312841.9 linkuse as main transcript	c.3214-601_3214-598dupCCGG		intron_variant		5		ENSP00000326765.8	O43593-2
HR	ENST00000522016.1 linkuse as main transcript	n.1417_1420dupCCGG		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000910

AC:

AN:

109850

Hom.:

AF XY:

0.0000167

AC XY:

AN XY:

60060

show subpopulations

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:

AN:

1355380

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

665540

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over