NM_005144.5:c.*303G>A

Variant names:

• chr8-22115397-C-T
• rs181310087
• NM_005144.5:c.*303G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_005144.5(HR):​c.*303G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 534,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: HR NM_005144.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.81
• Publications: 0 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]

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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000138 (21/152136) while in subpopulation AMR AF = 0.000589 (9/15286). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*303G>A		3_prime_UTR	Exon 19 of 19	NP_005135.2
	HR	NM_018411.4		c.*303G>A		3_prime_UTR	Exon 18 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.*303G>A		3_prime_UTR	Exon 19 of 19	ENSP00000370826.4	O43593-1
	HR	ENST00000680789.1		c.*303G>A		3_prime_UTR	Exon 20 of 20	ENSP00000505181.1	O43593-1
	HR	ENST00000902240.1		c.*303G>A		3_prime_UTR	Exon 17 of 17	ENSP00000572299.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000238 AC: 91 AN: 382146 Hom.: 0 Cov.: 0 AF XY: 0.000209 AC XY: 42 AN XY: 200522

African (AFR) AF: 0.00 AC: 0 AN: 11222

American (AMR) AF: 0.000976 AC: 16 AN: 16398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11844

East Asian (EAS) AF: 0.00 AC: 0 AN: 26138

South Asian (SAS) AF: 0.00 AC: 0 AN: 41634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1626

European-Non Finnish (NFE) AF: 0.000300 AC: 68 AN: 226528

Other (OTH) AF: 0.000314 AC: 7 AN: 22276

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41514

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67988

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000310

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Alopecia universalis congenita (1)
-	1	-	Atrichia with papular lesions (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		1.8

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: rs181310087; hg19: chr8-21972910;