8-22130635-G-C

Position:

• chr8-22130635-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001394132.1(HRURF):​c.74C>G​(p.Pro25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRURF NM_001394132.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.50

Genes affected

HRURF (HGNC:55085): (HR upstream open reading frame) Implicated in hypotrichosis 4. [provided by Alliance of Genome Resources, Apr 2022]

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22130635-G-C is Pathogenic according to our data. Variant chr8-22130635-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2001115.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRURF	NM_001394132.1	c.74C>G	p.Pro25Arg	missense_variant	1/1	ENST00000518377.3	NP_001381061.1
HR	NM_005144.5	c.-248C>G		5_prime_UTR_variant	1/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.-248C>G		5_prime_UTR_variant	1/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRURF	ENST00000518377.3	c.74C>G	p.Pro25Arg	missense_variant	1/1	4	NM_001394132.1	ENSP00000505144.1
HR	ENST00000381418.9	c.-248C>G		5_prime_UTR_variant	1/19	1	NM_005144.5	ENSP00000370826.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro25 amino acid residue in HRURF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20163456, 24261346). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2001115). This missense change has been observed in individuals with clinical features of autosomal dominant Marie Unna hereditary hypotrichosis (PMID: 28406533; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 25 of the HRURF protein (p.Pro25Arg). This variant occurs in an alternate reading frame HRURF in the HR gene as c.74C>G (p.Pro25Arg), and corresponds to NM_005144.4:c.-248C>G in the primary transcript. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-21988148;