8-22123705-C-T

Position:

• chr8-22123705-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005144.5(HR):​c.1859G>A​(p.Arg620Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,568,566 control chromosomes in the GnomAD database, including 855 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (37 hom., cov: 31)
  • Exomes 𝑓: 0.030 (818 hom.)
• Consequence: HR NM_005144.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006670356).
• BP6: Variant 8-22123705-C-T is Benign according to our data. Variant chr8-22123705-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 362507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-22123705-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.1859G>A	p.Arg620Gln	missense_variant	6/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.1859G>A	p.Arg620Gln	missense_variant	6/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.1859G>A	p.Arg620Gln	missense_variant	6/19	1	NM_005144.5	ENSP00000370826	P1
HR	ENST00000680789.1	c.1859G>A	p.Arg620Gln	missense_variant	7/20			ENSP00000505181	P1
HR	ENST00000312841.9	c.1859G>A	p.Arg620Gln	missense_variant	6/18	5		ENSP00000326765

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3332 AN: 151634 Hom.: 37 Cov.: 31

Gnomad AFR AF: 0.00599

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0241

GnomAD3 exomes AF: 0.0257 AC: 4847 AN: 188436 Hom.: 118 AF XY: 0.0286 AC XY: 2915 AN XY: 102082

Gnomad AFR exome AF: 0.00422

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.0000675

Gnomad SAS exome AF: 0.0562

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0303 AC: 42945 AN: 1416814 Hom.: 818 Cov.: 38 AF XY: 0.0313 AC XY: 21951 AN XY: 702064

Gnomad4 AFR exome AF: 0.00500

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.000131

Gnomad4 SAS exome AF: 0.0595

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.0308

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0220 AC: 3335 AN: 151752 Hom.: 37 Cov.: 31 AF XY: 0.0222 AC XY: 1644 AN XY: 74144

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.0260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0556

Gnomad4 FIN AF: 0.0334

Gnomad4 NFE AF: 0.0301

Gnomad4 OTH AF: 0.0229

Alfa AF: 0.0279 Hom.: 90

Bravo AF: 0.0198

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0277 AC: 238

ExAC AF: 0.0226 AC: 2713

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 22995991, 20981092, 9758627, 27884173, 17609203, 11410842) -
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 22, 2024	- -

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. -

Atrichia with papular lesions 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 256/12980=1.97% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.057	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0067	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.59	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.23
Sift	Benign	0.16	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.16
MPC		0.58
ClinPred		0.022	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs117197822; hg19: chr8-21981218;