rs7014851

Positions:

chr8-22119197-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 7330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-22119197-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
HR	NM_005144.5 linkuse as main transcript	c.3064A>G	p.Thr1022Ala	missense_variant	15/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4 linkuse as main transcript	c.3064A>G	p.Thr1022Ala	missense_variant	15/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9 linkuse as main transcript	c.3064A>G	p.Thr1022Ala	missense_variant	15/19	1	NM_005144.5	ENSP00000370826	P1	O43593-1
HR	ENST00000680789.1 linkuse as main transcript	c.3064A>G	p.Thr1022Ala	missense_variant	16/20			ENSP00000505181	P1	O43593-1
HR	ENST00000312841.9 linkuse as main transcript	c.3064A>G	p.Thr1022Ala	missense_variant	15/18	5		ENSP00000326765		O43593-2
HR	ENST00000522039.1 linkuse as main transcript	n.196A>G		non_coding_transcript_exon_variant	2/3	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

GnomAD3 exomes

AF:

0.0309

AC:

7746

AN:

250930

Hom.:

540

AF XY:

0.0263

AC XY:

3579

AN XY:

135826

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 SAS exome

AF:

0.00830

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

Gnomad4 AFR exome

AF:

0.250

Gnomad4 AMR exome

AF:

0.0265

Gnomad4 ASJ exome

AF:

0.0427

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00890

Gnomad4 FIN exome

AF:

0.0173

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.0328

GnomAD4 genome

AF:

0.0813

AC:

12371

AN:

152256

Hom.:

1288

Cov.:

AF XY:

0.0785

AC XY:

5844

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.244

Gnomad4 AMR

AF:

0.0481

Gnomad4 ASJ

AF:

0.0429

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00787

Gnomad4 FIN

AF:

0.0142

Gnomad4 NFE

AF:

0.0154

Gnomad4 OTH

AF:

0.0600

Alfa

AF:

0.0296

Hom.:

416

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2018	This variant is associated with the following publications: (PMID: 9736769, 10594736, 20981092, 9445480, 27884173, 17609203) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alopecia universalis congenita

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 01, 1998	- -

Atrichia with papular lesions

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

HR-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

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

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

MutationTaster

Benign

1.0

P;P

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

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