4-8868090-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_018942.3(HMX1):​c.650A>C​(p.Gln217Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: HMX1 NM_018942.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 4-8868090-T-G is Pathogenic according to our data. 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. Variant chr4-8868090-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMX1	NM_018942.3	c.650A>C	p.Gln217Pro	missense_variant	Exon 2 of 2	ENST00000400677.5	NP_061815.2
HMX1	NM_001306142.2	c.394+3131A>C		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>C	p.Gln217Pro	missense_variant	Exon 2 of 2	1	NM_018942.3	ENSP00000383516.3
HMX1	ENST00000506970.2	c.394+3131A>C		intron_variant	Intron 1 of 1	1		ENSP00000446997.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369020 Hom.: 0 Cov.: 34 AF XY: 0.00000148 AC XY: 1 AN XY: 676230

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: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oculoauricular syndrome Pathogenic:1

Jan 08, 2015

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	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.91
Sift	Benign	0.035	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.60		Loss of MoRF binding (P = 0.0561);
MVP		0.97
MPC		1.2
ClinPred		0.95	D
GERP RS		2.4
Varity_R		0.95
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876657398; hg19: chr4-8869816;