10-123136207-C-T

Variant names:

• chr10-123136207-C-T
• rs1314128260
• NM_001105574.2:c.157C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001105574.2(HMX3):​c.157C>T​(p.Arg53Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,228,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: HMX3 NM_001105574.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.683
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.157C>T	p.Arg53Trp	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.157C>T	p.Arg53Trp	missense	Exon 1 of 2	ENSP00000350549.4	A6NHT5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000326 AC: 4 AN: 1228570 Hom.: 0 Cov.: 36 AF XY: 0.00000499 AC XY: 3 AN XY: 600636

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25054

American (AMR) AF: 0.00 AC: 0 AN: 15336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17956

East Asian (EAS) AF: 0.00 AC: 0 AN: 29344

South Asian (SAS) AF: 0.0000222 AC: 1 AN: 45046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000300 AC: 3 AN: 1000304

Other (OTH) AF: 0.00 AC: 0 AN: 49530

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0404278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.054
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.68
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.17		Loss of methylation at R53 (P = 0.0267)
MVP		0.63
MPC		1.5
ClinPred		0.87	D
GERP RS		1.5
PromoterAI		0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.20
gMVP		0.46
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1314128260; hg19: chr10-124895723;