chr4-8868090-T-C

Variant names:

• chr4-8868090-T-C
• rs876657398
• NM_018942.3:c.650A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_018942.3(HMX1):​c.650A>G​(p.Gln217Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,369,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q217P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HMX1 NM_018942.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 0 publications found

Genes affected

HMX1 (HGNC:5017): (H6 family homeobox 1) This gene encodes a transcription factor that belongs to the H6 family of homeobox proteins. This protein can bind a 5'-CAAG-3' core DNA sequence, and it is involved in the development of craniofacial structures. Mutations in this gene cause oculoauricular syndrome, a disorder of the eye and external ear. [provided by RefSeq, Oct 2009]

HMX1 Gene-Disease associations (from GenCC):

• oculoauricular syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-8868090-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 192315.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMX1	NM_018942.3	c.650A>G	p.Gln217Arg	missense_variant	Exon 2 of 2	ENST00000400677.5	NP_061815.2
HMX1	NM_001306142.2	c.394+3131A>G		intron_variant	Intron 1 of 1		NP_001293071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMX1	ENST00000400677.5	c.650A>G	p.Gln217Arg	missense_variant	Exon 2 of 2	1	NM_018942.3	ENSP00000383516.3
HMX1	ENST00000506970.2	c.394+3131A>G		intron_variant	Intron 1 of 1	1		ENSP00000446997.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1369020 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 676230

African (AFR) AF: 0.00 AC: 0 AN: 29410

American (AMR) AF: 0.00 AC: 0 AN: 34154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24490

East Asian (EAS) AF: 0.00 AC: 0 AN: 33294

South Asian (SAS) AF: 0.00 AC: 0 AN: 76360

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068616

Other (OTH) AF: 0.00 AC: 0 AN: 56874

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.49	N
PhyloP100		2.6
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.52
Sift	Benign	0.043	D
Sift4G	Uncertain	0.030	D
Polyphen		0.21	B
Vest4		0.38
MutPred		0.59		Gain of MoRF binding (P = 0.0165);
MVP		0.94
MPC		2.0
ClinPred		0.91	D
GERP RS		2.4
Varity_R		0.41
gMVP		0.64
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs876657398; hg19: chr4-8869816;