8-22130707-A-T

Position:

• chr8-22130707-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001394132.1(HRURF):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22130707-A-T is Pathogenic according to our data. Variant chr8-22130707-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1335706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRURF	NM_001394132.1	c.2T>A	p.Met1?	start_lost	1/1	ENST00000518377.3	NP_001381061.1
HR	NM_005144.5	c.-320T>A		5_prime_UTR_variant	1/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.-320T>A		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.2T>A	p.Met1?	start_lost	1/1	4	NM_001394132.1	ENSP00000505144.1
HR	ENST00000381418.9	c.-320T>A		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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 06, 2022	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects HR function (PMID: 19122663). ClinVar contains an entry for this variant (Variation ID: 1335706). Disruption of the initiator codon has been observed in individual(s) with autosomal dominant Marie Unna hereditary hypotrichosis (PMID: 19122663, 20055871). 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 affects the initiator methionine of the HRURF mRNA. The next in-frame methionine is located at codon 72. This variant occurs in an alternate reading frame HRURF in the HR gene as c.2T>A (p.Met1?), and corresponds to NM_005144.4:c.-320T>A in the primary transcript. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Benign	0.92

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: chr8-21988220;