Variant 8-22114438-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005144.5(HR):c.*1262G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 150,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 0 hom. )

Consequence

HR
NM_005144.5 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -1.13

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HR	NM_005144.5 link	c.*1262G>C		3_prime_UTR_variant	Exon 19 of 19	ENST00000381418.9	NP_005135.2	O43593-1
HR	NM_018411.4 link	c.*1262G>C		3_prime_UTR_variant	Exon 18 of 18		NP_060881.2	O43593-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HR	ENST00000381418 link	c.*1262G>C	3_prime_UTR_variant	Exon 19 of 19	1	NM_005144.5	ENSP00000370826.4	O43593-1
HR	ENST00000680789 link	c.*1262G>C	3_prime_UTR_variant	Exon 20 of 20			ENSP00000505181.1	O43593-1
HR	ENST00000312841 link	c.*1262G>C	3_prime_UTR_variant	Exon 18 of 18	5		ENSP00000326765.8	O43593-2

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

248

AN:

149478

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000831

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000529

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00114

Gnomad MID

AF:

0.0130

Gnomad NFE

AF:

0.00257

Gnomad OTH

AF:

0.00243

GnomAD4 exome

AF:

0.00234

AC:

AN:

428

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

AN XY:

256

show subpopulations

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.167

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00165

AC:

247

AN:

149588

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

118

AN XY:

73184

show subpopulations

Gnomad4 AFR

AF:

0.000829

Gnomad4 AMR

AF:

0.000529

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00114

Gnomad4 NFE

AF:

0.00257

Gnomad4 OTH

AF:

0.00241

Alfa

AF:

0.000585

Hom.:

Bravo

AF:

0.00139

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrichia with papular lesions

Uncertain:1

Jan 13, 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. -

Alopecia universalis congenita

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.084

DANN

Benign

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over