rs7014851

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005144.5(HR):c.3064A>G(p.Thr1022Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,613,788 control chromosomes in the GnomAD database, including 2,682 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 1288 hom., cov: 33)

Exomes 𝑓: 0.021 ( 1394 hom. )

Consequence

HR
NM_005144.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 2.27

Publications

15 publications found

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 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

HR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028341115).

BP6

Variant 8-22119197-T-C is Benign according to our data. Variant chr8-22119197-T-C is described in ClinVar as Benign. ClinVar VariationId is 7330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HR	NM_005144.5 link	c.3064A>G	p.Thr1022Ala	missense_variant	Exon 15 of 19	ENST00000381418.9	NP_005135.2	O43593-1
HR	NM_018411.4 link	c.3064A>G	p.Thr1022Ala	missense_variant	Exon 15 of 18		NP_060881.2	O43593-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HR	ENST00000381418.9 link	c.3064A>G	p.Thr1022Ala	missense_variant	Exon 15 of 19	1	NM_005144.5	ENSP00000370826.4	O43593-1
HR	ENST00000680789.1 link	c.3064A>G	p.Thr1022Ala	missense_variant	Exon 16 of 20			ENSP00000505181.1	O43593-1
HR	ENST00000312841.9 link	c.3064A>G	p.Thr1022Ala	missense_variant	Exon 15 of 18	5		ENSP00000326765.8	O43593-2
HR	ENST00000522039.1 link	n.196A>G		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0813

AC:

12365

AN:

152138

Hom.:

1290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.244

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0481

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.0611

GnomAD2 exomes

AF:

0.0309

AC:

7746

AN:

250930

AF XY:

0.0263

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.0244

Gnomad ASJ exome

AF:

0.0447

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0149

Gnomad OTH exome

AF:

0.0276

GnomAD4 exome

AF:

0.0210

AC:

30693

AN:

1461532

Hom.:

1394

Cov.:

AF XY:

0.0198

AC XY:

14431

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.250

AC:

8386

AN:

33480

American (AMR)

AF:

0.0265

AC:

1184

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

1116

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.00890

AC:

768

AN:

86254

European-Finnish (FIN)

AF:

0.0173

AC:

917

AN:

53082

Middle Eastern (MID)

AF:

0.0354

AC:

204

AN:

5768

European-Non Finnish (NFE)

AF:

0.0145

AC:

16132

AN:

1112000

Other (OTH)

AF:

0.0328

AC:

1979

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1848

3697

5545

7394

9242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

756

1512

2268

3024

3780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0813

AC:

12371

AN:

152256

Hom.:

1288

Cov.:

AF XY:

0.0785

AC XY:

5844

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.244

AC:

10110

AN:

41498

American (AMR)

AF:

0.0481

AC:

736

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0429

AC:

149

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00787

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0142

AC:

151

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1048

AN:

68026

Other (OTH)

AF:

0.0600

AC:

127

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

504

1008

1511

2015

2519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0371

Hom.:

1439

Bravo

AF:

0.0937

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.250

AC:

1101

ESP6500EA

AF:

0.0160

AC:

138

ExAC

AF:

0.0346

AC:

4198

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0159

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9736769, 10594736, 20981092, 9445480, 27884173, 17609203) -

Alopecia universalis congenita

Uncertain:1Benign:1

Oct 01, 1998

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atrichia with papular lesions

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HR-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.053

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

N;N

PhyloP100

2.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.58

N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.014

MPC

0.16

ClinPred

0.0021

GERP RS

4.3

Varity_R

0.035

gMVP

0.62

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over