Genetic Variant HMX1:p.Ala334Pro (chr4-8867740-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018942.3(HMX1):c.1000G>C(p.Ala334Pro) 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 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HMX1
NM_018942.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.495

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3480128).

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.1000G>C	p.Ala334Pro	missense	Exon 2 of 2	NP_061815.2	Q9NP08
	HMX1	NM_001306142.2		c.394+3481G>C		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.1000G>C	p.Ala334Pro	missense	Exon 2 of 2	ENSP00000383516.3	Q9NP08
	HMX1	ENST00000506970.2	TSL:1	c.394+3481G>C		intron	N/A	ENSP00000446997.2	F1T0J4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1137798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

548726

African (AFR)

AF:

0.00

AC:

AN:

23620

American (AMR)

AF:

0.00

AC:

AN:

11896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16158

East Asian (EAS)

AF:

0.00

AC:

AN:

27050

South Asian (SAS)

AF:

0.00

AC:

AN:

31914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3384

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

954314

Other (OTH)

AF:

0.00

AC:

AN:

45852

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

Eigen

Benign

0.11

Eigen_PC

Benign

0.083

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.47

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.35

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.90

PhyloP100

0.49

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.74

REVEL

Uncertain

0.34

Sift

Uncertain

0.0050

Sift4G

Benign

0.21

Polyphen

1.0

Vest4

0.41

MutPred

0.41

Gain of disorder (P = 0.0537)

MVP

0.93

MPC

2.3

ClinPred

0.73

GERP RS

3.9

Varity_R

0.33

gMVP

0.50

Mutation Taster

=85/15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over