chr8-22115103-G-A

Variant names:

• chr8-22115103-G-A
• rs886062803
• NM_005144.5:c.*597C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005144.5(HR):​c.*597C>T variant causes a 3 prime UTR 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HR NM_005144.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.719
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

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.*597C>T		3_prime_UTR	Exon 19 of 19	NP_005135.2
	HR	NM_018411.4		c.*597C>T		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.*597C>T		3_prime_UTR	Exon 19 of 19	ENSP00000370826.4	O43593-1
	HR	ENST00000680789.1		c.*597C>T		3_prime_UTR	Exon 20 of 20	ENSP00000505181.1	O43593-1
	HR	ENST00000902240.1		c.*597C>T		3_prime_UTR	Exon 17 of 17	ENSP00000572299.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8876 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4612

African (AFR) AF: 0.00 AC: 0 AN: 170

American (AMR) AF: 0.00 AC: 0 AN: 1320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 132

East Asian (EAS) AF: 0.00 AC: 0 AN: 400

South Asian (SAS) AF: 0.00 AC: 0 AN: 652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 5528

Other (OTH) AF: 0.00 AC: 0 AN: 442

GnomAD4 genome Cov.: 33

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	-0.67
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		0.72

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: rs886062803; hg19: chr8-21972616;