Genetic Variant HMX3:p.Ala71Glu (chr10-123136262-C-A) – 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_001105574.2(HMX3):c.212C>A(p.Ala71Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A71V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HMX3
NM_001105574.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.56

Publications

1 publications found

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:

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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=0.28491026).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105574.2. 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
	HMX3	NM_001105574.2	MANE Select	c.212C>A	p.Ala71Glu	missense	Exon 1 of 2	NP_001099044.1	A6NHT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMX3	ENST00000357878.7	TSL:2 MANE Select	c.212C>A	p.Ala71Glu	missense	Exon 1 of 2	ENSP00000350549.4	A6NHT5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1217656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

595018

African (AFR)

AF:

0.00

AC:

AN:

23888

American (AMR)

AF:

0.00

AC:

AN:

11014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17986

East Asian (EAS)

AF:

0.00

AC:

AN:

27794

South Asian (SAS)

AF:

0.00

AC:

AN:

46440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4038

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

995934

Other (OTH)

AF:

0.00

AC:

AN:

49184

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.065

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.1

PhyloP100

2.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.32

REVEL

Benign

0.27

Sift

Uncertain

0.0010

Sift4G

Benign

0.21

Polyphen

0.069

Vest4

0.44

MutPred

0.32

Gain of solvent accessibility (P = 0.0411)

MVP

0.83

MPC

0.86

ClinPred

0.64

GERP RS

3.0

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.38

gMVP

0.52

Mutation Taster

=95/5

polymorphism

(source)

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

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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