8-22130707-A-T

Variant names:

• chr8-22130707-A-T
• rs387906382
• NM_001394132.1:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV003312227: Experimental studies have shown that disruption of the initiator codon affects HR function (PMID:19122663).".

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• alopecia universalis congenita

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• atrichia with papular lesions

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• hypotrichosis 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Marie Unna hereditary hypotrichosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003312227: Experimental studies have shown that disruption of the initiator codon affects HR function (PMID: 19122663).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 1335706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394132.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRURF	NM_001394132.1	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 1	NP_001381061.1	P0DUH7
	HR	NM_005144.5	MANE Select	c.-320T>A		5_prime_UTR	Exon 1 of 19	NP_005135.2
	HR	NM_018411.4		c.-320T>A		5_prime_UTR	Exon 1 of 18	NP_060881.2	O43593-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRURF	ENST00000518377.3	TSL:4 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 1	ENSP00000505144.1	P0DUH7
	HR	ENST00000381418.9	TSL:1 MANE Select	c.-320T>A		5_prime_UTR	Exon 1 of 19	ENSP00000370826.4	O43593-1
	HR	ENST00000680789.1		c.-320T>A		5_prime_UTR	Exon 2 of 20	ENSP00000505181.1	O43593-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Benign	0.92
PhyloP100		4.0
PromoterAI		-0.20	Neutral
Mutation Taster		=32/268	disease causing

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

Other links and lift over

dbSNP: rs387906382; hg19: chr8-21988220;