Genetic Variant HMX3:p.Arg131Gly (chr10-123136441-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001105574.2(HMX3):c.391C>G(p.Arg131Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,445,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HMX3
NM_001105574.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.121

Variant links:

Genes affected

HMX3 (HGNC:5019): (H6 family homeobox 3) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in ear development and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including embryo implantation; maternal process involved in female pregnancy; and neuromuscular process controlling balance. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HMX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02057165).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMX3	NM_001105574.2 link	c.391C>G	p.Arg131Gly	missense_variant	Exon 1 of 2	ENST00000357878.7	NP_001099044.1	A6NHT5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMX3	ENST00000357878.7 link	c.391C>G	p.Arg131Gly	missense_variant	Exon 1 of 2	2	NM_001105574.2	ENSP00000350549.4		A6NHT5

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151872

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:

0.00137

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000629

AC:

AN:

127130

Hom.:

AF XY:

0.0000694

AC XY:

AN XY:

72040

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00104

Gnomad SAS exome

AF:

0.0000608

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1293886

Hom.:

Cov.:

AF XY:

0.0000188

AC XY:

AN XY:

637676

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000595

Gnomad4 SAS exome

AF:

0.0000321

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.75e-7

Gnomad4 OTH exome

AF:

0.0000192

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00138

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000924

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.391C>G (p.R131G) alteration is located in exon 1 (coding exon 1) of the HMX3 gene. This alteration results from a C to G substitution at nucleotide position 391, causing the arginine (R) at amino acid position 131 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.021

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.059

Polyphen

0.0010

Vest4

0.48

MutPred

0.24

Gain of catalytic residue at R131 (P = 0.0511);

MVP

0.97

MPC

1.2

ClinPred

0.14

GERP RS

1.9

Varity_R

0.40

gMVP

0.49

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over