rs121434449

Positions:

• chr8-22123727-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005144.5(HR):​c.1837C>T​(p.Arg613*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: HR NM_005144.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.00700

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 11 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
• PP5: Variant 8-22123727-G-A is Pathogenic according to our data. Variant chr8-22123727-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7335.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.1837C>T	p.Arg613*	stop_gained	6/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.1837C>T	p.Arg613*	stop_gained	6/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.1837C>T	p.Arg613*	stop_gained	6/19	1	NM_005144.5	ENSP00000370826.4
HR	ENST00000680789.1	c.1837C>T	p.Arg613*	stop_gained	7/20			ENSP00000505181.1
HR	ENST00000312841.9	c.1837C>T	p.Arg613*	stop_gained	6/18	5		ENSP00000326765.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437464 Hom.: 0 Cov.: 37 AF XY: 0.00000280 AC XY: 2 AN XY: 713918

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 FIN exome AF: 0.0000235

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrichia with papular lesions Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.34	N
Vest4		0.83
GERP RS		-0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs121434449; hg19: chr8-21981240;