X-101657246-C-T

Variant names:

• chrX-101657246-C-T
• rs782469676
• NM_177949.4:c.343G>A
• ARMCX2 p.Ala115Thr

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177949.4(ARMCX2):​c.343G>A​(p.Ala115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,964 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A115S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ARMCX2 NM_177949.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 0 publications found

Genes affected

ARMCX2 (HGNC:16869): (armadillo repeat containing X-linked 2) This gene encodes a protein containing a potential N-terminal transmembrane domain and multiple armadillo (arm) repeats. Proteins containing arm repeats are involved in development, maintenance of tissue integrity, and tumorigenesis. This gene is located in a cluster of related genes on chromosome X. There is a pseudogene for this gene on chromosome 7. Alternative splicing in the 5' UTR results in multiple transcript variants encoding the same protein. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10088804).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177949.4. 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
	ARMCX2	NM_177949.4	MANE Select	c.343G>A	p.Ala115Thr	missense	Exon 6 of 6	NP_808818.1	Q7L311
	ARMCX2	NM_001282231.2		c.343G>A	p.Ala115Thr	missense	Exon 6 of 6	NP_001269160.1	Q7L311
	ARMCX2	NM_014782.7		c.343G>A	p.Ala115Thr	missense	Exon 5 of 5	NP_055597.1	Q7L311

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMCX2	ENST00000356824.9	TSL:1 MANE Select	c.343G>A	p.Ala115Thr	missense	Exon 6 of 6	ENSP00000349281.4	Q7L311
	ARMCX2	ENST00000328766.9	TSL:1	c.343G>A	p.Ala115Thr	missense	Exon 5 of 5	ENSP00000331662.5	Q7L311
	ARMCX2	ENST00000330154.6	TSL:1	c.343G>A	p.Ala115Thr	missense	Exon 3 of 3	ENSP00000328631.2	Q7L311

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091964 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 358554

⚠️ 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: 26283

American (AMR) AF: 0.00 AC: 0 AN: 34914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19140

East Asian (EAS) AF: 0.00 AC: 0 AN: 30025

South Asian (SAS) AF: 0.00 AC: 0 AN: 53664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4109

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 837663

Other (OTH) AF: 0.00 AC: 0 AN: 45744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.084
Sift	Benign	0.30	T
Sift4G	Benign	0.098	T
Varity_R		0.083
gMVP		0.078
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs782469676; hg19: chrX-100912232;