8-22116400-A-T

Variant names:

• chr8-22116400-A-T
• rs121434448
• NM_005144.5:c.3407T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 5 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: Likely_pathogenic. The variant received 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 CliVar as Pathogenic. Clinvar id is 7331.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22116400-A-T is described in CliVar as Pathogenic. Clinvar id is 7331.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22116400-A-T is described in CliVar as Pathogenic. Clinvar id is 7331.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22116400-A-T is described in CliVar as Pathogenic. Clinvar id is 7331.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22116400-A-T is described in CliVar as Pathogenic. Clinvar id is 7331.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-22116400-A-T is described in CliVar 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 rank	MANE	Protein	UniProt
HR	NM_005144.5	c.3407T>A	p.Val1136Asp	missense_variant	Exon 18 of 19	ENST00000381418.9	NP_005135.2
HR	NM_018411.4	c.3242T>A	p.Val1081Asp	missense_variant	Exon 17 of 18		NP_060881.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.3407T>A	p.Val1136Asp	missense_variant	Exon 18 of 19	1	NM_005144.5	ENSP00000370826.4
HR	ENST00000680789.1	c.3407T>A	p.Val1136Asp	missense_variant	Exon 19 of 20			ENSP00000505181.1
HR	ENST00000312841.9	c.3242T>A	p.Val1081Asp	missense_variant	Exon 17 of 18	5		ENSP00000326765.8
HR	ENST00000522016.1	n.1600T>A		non_coding_transcript_exon_variant	Exon 2 of 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

Oct 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.
PhyloP100		3.4
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
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434448; hg19: chr8-21973913;