8-22115280-G-A

Variant names:

• chr8-22115280-G-A
• rs763478016
• NM_005144.5:c.*420C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_005144.5(HR):​c.*420C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 299,226 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 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: HR NM_005144.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0270
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00021 (32/152340) while in subpopulation SAS AF = 0.000622 (3/4824). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.*420C>T		3_prime_UTR	Exon 19 of 19	NP_005135.2
	HR	NM_018411.4		c.*420C>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.*420C>T		3_prime_UTR	Exon 19 of 19	ENSP00000370826.4	O43593-1
	HR	ENST00000680789.1		c.*420C>T		3_prime_UTR	Exon 20 of 20	ENSP00000505181.1	O43593-1
	HR	ENST00000902240.1		c.*420C>T		3_prime_UTR	Exon 17 of 17	ENSP00000572299.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000300 AC: 44 AN: 146886 Hom.: 0 Cov.: 0 AF XY: 0.000336 AC XY: 26 AN XY: 77492

African (AFR) AF: 0.000201 AC: 1 AN: 4978

American (AMR) AF: 0.00 AC: 0 AN: 7484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3796

East Asian (EAS) AF: 0.00 AC: 0 AN: 7268

South Asian (SAS) AF: 0.000762 AC: 17 AN: 22322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 582

European-Non Finnish (NFE) AF: 0.000268 AC: 23 AN: 85800

Other (OTH) AF: 0.000378 AC: 3 AN: 7946

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74502

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.000219

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	-0.89
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		0.027
Mutation Taster		=100/0	polymorphism

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: rs763478016; hg19: chr8-21972793;