Variant 8-22116337-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005144.5(HR):c.3470C>A(p.Pro1157His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1157R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HR
NM_005144.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32580435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5 linkuse as main transcript	c.3470C>A	p.Pro1157His	missense_variant	18/19	ENST00000381418.9	NP_005135.2	O43593-1
HR	NM_018411.4 linkuse as main transcript	c.3305C>A	p.Pro1102His	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>A	p.Pro1157His	missense_variant	18/19	1	NM_005144.5	ENSP00000370826.4	O43593-1
HR	ENST00000680789.1 linkuse as main transcript	c.3470C>A	p.Pro1157His	missense_variant	19/20			ENSP00000505181.1	O43593-1
HR	ENST00000312841.9 linkuse as main transcript	c.3305C>A	p.Pro1102His	missense_variant	17/18	5		ENSP00000326765.8	O43593-2
HR	ENST00000522016.1 linkuse as main transcript	n.1663C>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249812

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460548

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.0034

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

T;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.72

N;N

REVEL

Benign

0.20

Sift

Benign

0.062

T;T

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.62

P;P

Vest4

0.40

MutPred

0.38

Loss of loop (P = 0.0374);.;

MVP

0.88

MPC

0.39

ClinPred

0.79

GERP RS

5.1

Varity_R

0.10

gMVP

0.59

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over