10-123136381-G-C

Variant names:

• chr10-123136381-G-C
• NM_001105574.2:c.331G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001105574.2(HMX3):​c.331G>C​(p.Glu111Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMX3	NM_001105574.2	c.331G>C	p.Glu111Gln	missense_variant	Exon 1 of 2	ENST00000357878.7	NP_001099044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMX3	ENST00000357878.7	c.331G>C	p.Glu111Gln	missense_variant	Exon 1 of 2	2	NM_001105574.2	ENSP00000350549.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1412154 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 701598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331G>C (p.E111Q) alteration is located in exon 1 (coding exon 1) of the HMX3 gene. This alteration results from a G to C substitution at nucleotide position 331, causing the glutamic acid (E) at amino acid position 111 to be replaced by a glutamine (Q). 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.46
MutPred		0.46		Loss of solvent accessibility (P = 0.0172);
MVP		0.78
MPC		1.6
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.51
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-124895897;