chr8-22114944-C-A

Variant names:

• chr8-22114944-C-A
• rs116456103
• NM_005144.5:c.*756G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005144.5(HR):​c.*756G>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 0.00524 in 152,342 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HR NM_005144.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.29
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-22114944-C-A is Benign according to our data. Variant chr8-22114944-C-A is described in ClinVar as Benign. ClinVar VariationId is 911826.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00524 (799/152342) while in subpopulation AFR AF = 0.0183 (760/41574). AF 95% confidence interval is 0.0172. There are 11 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

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.*756G>T		3_prime_UTR	Exon 19 of 19	NP_005135.2
	HR	NM_018411.4		c.*756G>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.*756G>T		3_prime_UTR	Exon 19 of 19	ENSP00000370826.4	O43593-1
	HR	ENST00000680789.1		c.*756G>T		3_prime_UTR	Exon 20 of 20	ENSP00000505181.1	O43593-1
	HR	ENST00000312841.9	TSL:5	c.*756G>T		3_prime_UTR	Exon 18 of 18	ENSP00000326765.8	O43593-2

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152224 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 538 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 334

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 34

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.00 AC: 0 AN: 16

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 416

Other (OTH) AF: 0.00 AC: 0 AN: 30

GnomAD4 genome AF: 0.00524 AC: 799 AN: 152342 Hom.: 11 Cov.: 33 AF XY: 0.00506 AC XY: 377 AN XY: 74494

African (AFR) AF: 0.0183 AC: 760 AN: 41574

American (AMR) AF: 0.00137 AC: 21 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00304 Hom.: 1

Bravo AF: 0.00575

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	-0.73
CADD	Benign	0.18
DANN	Benign	0.82
PhyloP100		-2.3
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: rs116456103; hg19: chr8-21972457;