rs6557841

Variant names:

• chr8-22131002-A-C
• rs6557841
• NM_005144.5:c.-615T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005144.5(HR):​c.-615T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,186 control chromosomes in the GnomAD database, including 32,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32470 hom., cov: 35)
  • Exomes 𝑓: 0.59 (16 hom.)
• Consequence: HR NM_005144.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.213
• Publications: 7 publications found

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]

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

HRURF Gene-Disease associations (from GenCC):

• hypotrichosis 4

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 8-22131002-A-C is Benign according to our data. Variant chr8-22131002-A-C is described in ClinVar as Benign. ClinVar VariationId is 362542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005144.5. 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
	HR	NM_005144.5	MANE Select	c.-615T>G		5_prime_UTR	Exon 1 of 19	NP_005135.2
	HRURF	NM_001394132.1	MANE Select	c.-294T>G		5_prime_UTR	Exon 1 of 1	NP_001381061.1	P0DUH7
	HR	NM_018411.4		c.-615T>G		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
	HR	ENST00000381418.9	TSL:1 MANE Select	c.-615T>G		5_prime_UTR	Exon 1 of 19	ENSP00000370826.4	O43593-1
	HRURF	ENST00000518377.3	TSL:4 MANE Select	c.-294T>G		5_prime_UTR	Exon 1 of 1	ENSP00000505144.1	P0DUH7
	HR	ENST00000680789.1		c.-615T>G		5_prime_UTR	Exon 2 of 20	ENSP00000505181.1	O43593-1

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98276 AN: 151980 Hom.: 32419 Cov.: 35

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.615

GnomAD4 exome AF: 0.587 AC: 54 AN: 92 Hom.: 16 Cov.: 0 AF XY: 0.575 AC XY: 46 AN XY: 80

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 3 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.566 AC: 43 AN: 76

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.647 AC: 98385 AN: 152094 Hom.: 32470 Cov.: 35 AF XY: 0.645 AC XY: 47941 AN XY: 74366

African (AFR) AF: 0.768 AC: 31890 AN: 41536

American (AMR) AF: 0.547 AC: 8368 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2244 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2047 AN: 5140

South Asian (SAS) AF: 0.655 AC: 3161 AN: 4826

European-Finnish (FIN) AF: 0.619 AC: 6567 AN: 10602

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42083 AN: 67914

Other (OTH) AF: 0.616 AC: 1301 AN: 2112

Alfa AF: 0.629 Hom.: 22546

Bravo AF: 0.643

Asia WGS AF: 0.526 AC: 1831 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alopecia universalis congenita (1)
-	-	1	Atrichia with papular lesions (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		-0.21
PromoterAI		-0.094	Neutral
Mutation Taster		=255/45	polymorphism (auto)

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: rs6557841; hg19: chr8-21988515; COSMIC: COSV57192037; COSMIC: COSV57192037;