8-22115101-A-C

Position:

chr8-22115101-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005144.5(HR):c.*599T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 160,730 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0099 ( 17 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 0 hom. )

Consequence

HR
NM_005144.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.342

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 8-22115101-A-C is Benign according to our data. Variant chr8-22115101-A-C is described in ClinVar as [Benign]. Clinvar id is 908876.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00992 (1511/152350) while in subpopulation AFR AF= 0.0336 (1397/41588). AF 95% confidence interval is 0.0321. There are 17 homozygotes in gnomad4. There are 729 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5 linkuse as main transcript	c.*599T>G		3_prime_UTR_variant	19/19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4 linkuse as main transcript	c.*599T>G		3_prime_UTR_variant	18/18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9 linkuse as main transcript	c.*599T>G	3_prime_UTR_variant	19/19	1	NM_005144.5	ENSP00000370826	P1	O43593-1
HR	ENST00000312841.9 linkuse as main transcript	c.*599T>G	3_prime_UTR_variant	18/18	5		ENSP00000326765		O43593-2
HR	ENST00000680789.1 linkuse as main transcript	c.*599T>G	3_prime_UTR_variant	20/20			ENSP00000505181	P1	O43593-1
HR	ENST00000522016.1 linkuse as main transcript	n.2362T>G	non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00995

AC:

1514

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0337

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00716

GnomAD4 exome

AF:

0.000955

AC:

AN:

8380

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

4388

show subpopulations

Gnomad4 AFR exome

AF:

0.0290

Gnomad4 AMR exome

AF:

0.000809

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000191

Gnomad4 OTH exome

AF:

0.00452

GnomAD4 genome

AF:

0.00992

AC:

1511

AN:

152350

Hom.:

Cov.:

AF XY:

0.00978

AC XY:

729

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0336

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.00440

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Atrichia with papular lesions

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Alopecia universalis congenita

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.82

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