rs201030061

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005144.5(HR):c.3470C>G(p.Pro1157Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,612,822 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 250 hom. )

Consequence

HR
NM_005144.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.21

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:

HR (HGNC:):

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=0.0031084716).

BP6

Variant 8-22116337-G-C is Benign according to our data. Variant chr8-22116337-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 362475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-22116337-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0636 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.3470C>G	p.Pro1157Arg	missense_variant	18/19	ENST00000381418.9	NP_005135.2	O43593-1
HR	NM_018411.4 linkuse as main transcript	c.3305C>G	p.Pro1102Arg	missense_variant	17/18		NP_060881.2	O43593-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HR	ENST00000381418.9 linkuse as main transcript	c.3470C>G	p.Pro1157Arg	missense_variant	18/19	1	NM_005144.5	ENSP00000370826.4	O43593-1
HR	ENST00000680789.1 linkuse as main transcript	c.3470C>G	p.Pro1157Arg	missense_variant	19/20			ENSP00000505181.1	O43593-1
HR	ENST00000312841.9 linkuse as main transcript	c.3305C>G	p.Pro1102Arg	missense_variant	17/18	5		ENSP00000326765.8	O43593-2
HR	ENST00000522016.1 linkuse as main transcript	n.1663C>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

352

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0693

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00883

AC:

2206

AN:

249812

Hom.:

AF XY:

0.0118

AC XY:

1594

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0708

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.00361

GnomAD4 exome

AF:

0.00430

AC:

6284

AN:

1460548

Hom.:

250

Cov.:

AF XY:

0.00623

AC XY:

4528

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0686

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.00494

GnomAD4 genome

AF:

0.00232

AC:

354

AN:

152274

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

271

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0697

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000536

Hom.:

Bravo

AF:

0.000457

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00952

AC:

1156

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Atrichia with papular lesions

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Alopecia universalis congenita

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Intellectual disability, autosomal dominant 14

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The homozygous p.Pro1157Arg variant in HR has been identified in at least 2 individuals with atrichia with papular lesions (PMID: 21919222), but has also been identified in >6% of South Asian chromosomes and 52 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for atrichia with papular lesions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Benign

0.029

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

4.2

N;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

T;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.18

B;B

Vest4

0.41

MVP

0.82

MPC

0.27

ClinPred

0.052

GERP RS

5.1

Varity_R

0.085

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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