Genetic Variant HMX1:p.Ala334Gly (chr4-8867739-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018942.3(HMX1):c.1001C>G(p.Ala334Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,291,174 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 2 hom. )

Consequence

HMX1
NM_018942.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14915389).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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>G	p.Ala334Gly	missense	Exon 2 of 2	NP_061815.2	Q9NP08
	HMX1	NM_001306142.2		c.394+3482C>G		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>G	p.Ala334Gly	missense	Exon 2 of 2	ENSP00000383516.3	Q9NP08
	HMX1	ENST00000506970.2	TSL:1	c.394+3482C>G		intron	N/A	ENSP00000446997.2	F1T0J4

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000591

AC:

AN:

16920

AF XY:

0.000100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000781

AC:

AN:

1139094

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

549430

show subpopulations

African (AFR)

AF:

0.0000423

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:

0.00165

AC:

AN:

32090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23694

Middle Eastern (MID)

AF:

0.000587

AC:

AN:

3408

European-Non Finnish (NFE)

AF:

0.0000220

AC:

AN:

955098

Other (OTH)

AF:

0.000262

AC:

AN:

45888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00103

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67996

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000169

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.90

PhyloP100

2.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.9

REVEL

Benign

0.16

Sift

Uncertain

0.0050

Sift4G

Benign

0.33

Polyphen

0.90

Vest4

0.20

MutPred

0.33

Loss of glycosylation at S336 (P = 0.0657)

MVP

0.92

MPC

1.8

ClinPred

0.14

GERP RS

3.1

Varity_R

0.21

gMVP

0.39

Mutation Taster

=86/14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over