rs201030061

Variant summary

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

The NM_005144.5(HR):ā€‹c.3470C>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0023 ( 11 hom., cov: 32)
Exomes š‘“: 0.0043 ( 250 hom. )

Consequence

HR
NM_005144.5 missense

Scores

4
14

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]

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
HRNM_005144.5 linkuse as main transcriptc.3470C>G p.Pro1157Arg missense_variant 18/19 ENST00000381418.9 NP_005135.2 O43593-1
HRNM_018411.4 linkuse as main transcriptc.3305C>G p.Pro1102Arg missense_variant 17/18 NP_060881.2 O43593-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HRENST00000381418.9 linkuse as main transcriptc.3470C>G p.Pro1157Arg missense_variant 18/191 NM_005144.5 ENSP00000370826.4 O43593-1
HRENST00000680789.1 linkuse as main transcriptc.3470C>G p.Pro1157Arg missense_variant 19/20 ENSP00000505181.1 O43593-1
HRENST00000312841.9 linkuse as main transcriptc.3305C>G p.Pro1102Arg missense_variant 17/185 ENSP00000326765.8 O43593-2
HRENST00000522016.1 linkuse as main transcriptn.1663C>G non_coding_transcript_exon_variant 2/32

Frequencies

GnomAD3 genomes
AF:
0.00231
AC:
352
AN:
152156
Hom.:
11
Cov.:
32
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.:
88
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.:
31
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.:
11
Cov.:
32
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.:
0
Bravo
AF:
0.000457
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Atrichia with papular lesions Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Alopecia universalis congenita Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterresearchBroad 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
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
19
DANN
Benign
0.30
DEOGEN2
Benign
0.029
T;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.018
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.79
T;T
MetaRNN
Benign
0.0031
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.1
L;.
PrimateAI
Benign
0.28
T
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
T
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.

Other links and lift over

dbSNP: rs201030061; hg19: chr8-21973850; API