rs201030061

Variant names:

• chr8-22116337-G-C
• rs201030061
• NM_005144.5:c.3470C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-22116337-G-C
• chr8-22116337-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.21
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 362475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HR	NM_005144.5	MANE Select	c.3470C>G	p.Pro1157Arg	missense	Exon 18 of 19	NP_005135.2
	HR	NM_018411.4		c.3305C>G	p.Pro1102Arg	missense	Exon 17 of 18	NP_060881.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HR	ENST00000381418.9	TSL:1 MANE Select	c.3470C>G	p.Pro1157Arg	missense	Exon 18 of 19	ENSP00000370826.4
	HR	ENST00000680789.1		c.3470C>G	p.Pro1157Arg	missense	Exon 19 of 20	ENSP00000505181.1
	HR	ENST00000902240.1		c.3419C>G	p.Pro1140Arg	missense	Exon 16 of 17	ENSP00000572299.1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152156 Hom.: 11 Cov.: 32

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

GnomAD2 exomes AF: 0.00883 AC: 2206 AN: 249812 AF XY: 0.0118

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33446

American (AMR) AF: 0.000336 AC: 15 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0686 AC: 5915 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00288 AC: 14 AN: 4866

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111894

Other (OTH) AF: 0.00494 AC: 298 AN: 60284

GnomAD4 genome AF: 0.00232 AC: 354 AN: 152274 Hom.: 11 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74448

African (AFR) AF: 0.000144 AC: 6 AN: 41538

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0697 AC: 336 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Alopecia universalis congenita (1)
-	-	1	Atrichia with papular lesions (1)
-	-	1	Intellectual disability, autosomal dominant 14 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.2	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.18	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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs201030061; hg19: chr8-21973850;