X-101657159-C-T

Variant names:

• chrX-101657159-C-T
• rs149321969
• NM_177949.4:c.430G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_177949.4(ARMCX2):​c.430G>A​(p.Gly144Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,073,677 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: ARMCX2 NM_177949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.769

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06587666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMCX2	NM_177949.4	c.430G>A	p.Gly144Arg	missense_variant	Exon 6 of 6	ENST00000356824.9	NP_808818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMCX2	ENST00000356824.9	c.430G>A	p.Gly144Arg	missense_variant	Exon 6 of 6	1	NM_177949.4	ENSP00000349281.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000279 AC: 3 AN: 1073677 Hom.: 0 Cov.: 33 AF XY: 0.00000288 AC XY: 1 AN XY: 347363

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: 0.0000195

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.430G>A (p.G144R) alteration is located in exon 6 (coding exon 1) of the ARMCX2 gene. This alteration results from a G to A substitution at nucleotide position 430, causing the glycine (G) at amino acid position 144 to be replaced by an arginine (R). 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	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0040
DANN	Benign	0.53
DEOGEN2	Benign	0.015	T;T;T;T;T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.42	.;.;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;.;.
Polyphen		0.0010	B;B;B;.;.
Vest4		0.047
MutPred		0.36		Loss of catalytic residue at V145 (P = 0.0396);Loss of catalytic residue at V145 (P = 0.0396);Loss of catalytic residue at V145 (P = 0.0396);Loss of catalytic residue at V145 (P = 0.0396);Loss of catalytic residue at V145 (P = 0.0396);
MVP		0.082
MPC		0.44
ClinPred		0.042	T
GERP RS		-9.6
Varity_R		0.071
gMVP		0.079

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

LitVar

Other links and lift over

dbSNP: rs149321969; hg19: chrX-100912145;