8-22116400-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005144.5(HR):c.3407T>A(p.Val1136Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1136A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HR NM_005144.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.36

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 8-22116400-A-T is Pathogenic according to our data. Variant chr8-22116400-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 7331.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HR	NM_005144.5	c.3407T>A	p.Val1136Asp	missense_variant	18/19	ENST00000381418.9
HR	NM_018411.4	c.3242T>A	p.Val1081Asp	missense_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HR	ENST00000381418.9	c.3407T>A	p.Val1136Asp	missense_variant	18/19	1	NM_005144.5	P1
HR	ENST00000680789.1	c.3407T>A	p.Val1136Asp	missense_variant	19/20			P1
HR	ENST00000312841.9	c.3242T>A	p.Val1081Asp	missense_variant	17/18	5
HR	ENST00000522016.1	n.1600T>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alopecia universalis congenita Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.4	D;N
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.89		Loss of sheet (P = 0.0181);.;
MVP		0.96
MPC		0.87
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121434448; hg19: chr8-21973913;