Genetic Variant HMX1:p.Ala334Val (chr4-8867739-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018942.3(HMX1):c.1001C>T(p.Ala334Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,139,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A334T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HMX1
NM_018942.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

Publications

0 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

HMX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15301895).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018942.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMX1	NM_018942.3	MANE Select	c.1001C>T	p.Ala334Val	missense	Exon 2 of 2	NP_061815.2	Q9NP08
	HMX1	NM_001306142.2		c.394+3482C>T		intron	N/A	NP_001293071.1	F1T0J4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMX1	ENST00000400677.5	TSL:1 MANE Select	c.1001C>T	p.Ala334Val	missense	Exon 2 of 2	ENSP00000383516.3	Q9NP08
	HMX1	ENST00000506970.2	TSL:1	c.394+3482C>T		intron	N/A	ENSP00000446997.2	F1T0J4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1139094

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

549428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23652

American (AMR)

AF:

0.00

AC:

AN:

11970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16214

East Asian (EAS)

AF:

0.00

AC:

AN:

27080

South Asian (SAS)

AF:

0.00

AC:

AN:

32090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3408

European-Non Finnish (NFE)

AF:

0.0000230

AC:

AN:

955098

Other (OTH)

AF:

0.00

AC:

AN:

45888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-0.080

PhyloP100

2.1

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.17

REVEL

Benign

0.095

Sift

Benign

0.20

Sift4G

Benign

0.40

Polyphen

0.14

Vest4

0.36

MutPred

0.32

Gain of relative solvent accessibility (P = 0.0522)

MVP

0.85

MPC

1.8

ClinPred

0.60

GERP RS

3.1

Varity_R

0.068

gMVP

0.45

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over