rs140387885

Variant names:

• chr8-22114796-G-A
• rs140387885
• NM_005144.5:c.*904C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-22114796-G-A
• chr8-22114796-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_005144.5(HR):​c.*904C>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 0.00067 in 152,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., 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: 1.20
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00067 (102/152350) while in subpopulation NFE AF = 0.000794 (54/68026). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HR	NM_005144.5	c.*904C>T		3_prime_UTR_variant	Exon 19 of 19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.*904C>T		3_prime_UTR_variant	Exon 18 of 18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.*904C>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_005144.5	ENSP00000370826.4
HR	ENST00000680789.1	c.*904C>T		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505181.1
HR	ENST00000312841.9	c.*904C>T		3_prime_UTR_variant	Exon 18 of 18	5		ENSP00000326765.8

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 190 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 146

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 156

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74504

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000689 Hom.: 0

Bravo AF: 0.000438

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alopecia universalis congenita Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Atrichia with papular lesions Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs140387885; hg19: chr8-21972309;