X-101656765-G-A

Variant names:

• chrX-101656765-G-A
• rs782372258
• NM_177949.4:c.824C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_177949.4(ARMCX2):​c.824C>T​(p.Thr275Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,209,550 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000029 (0 hom. 10 hem.)
• Consequence: ARMCX2 NM_177949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.612

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028307527).
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMCX2	NM_177949.4	c.824C>T	p.Thr275Ile	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.824C>T	p.Thr275Ile	missense_variant	Exon 6 of 6	1	NM_177949.4	ENSP00000349281.4
ARMCX2	ENST00000328766.9	c.824C>T	p.Thr275Ile	missense_variant	Exon 5 of 5	1		ENSP00000331662.5
ARMCX2	ENST00000330154.6	c.824C>T	p.Thr275Ile	missense_variant	Exon 3 of 3	1		ENSP00000328631.2

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111247 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 33409

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000567

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000665

GnomAD3 exomes AF: 0.0000982 AC: 18 AN: 183278 Hom.: 0 AF XY: 0.0000886 AC XY: 6 AN XY: 67736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00108

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000291 AC: 32 AN: 1098251 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 10 AN XY: 363605

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000430

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111299 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 33471

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000569

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000657

Bravo AF: 0.0000227

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.824C>T (p.T275I) alteration is located in exon 6 (coding exon 1) of the ARMCX2 gene. This alteration results from a C to T substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by an isoleucine (I). 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	0.30
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	.;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.044
MutPred		0.30		Loss of glycosylation at T275 (P = 0.0273);Loss of glycosylation at T275 (P = 0.0273);Loss of glycosylation at T275 (P = 0.0273);
MVP		0.39
MPC		0.69
ClinPred		0.13	T
GERP RS		4.5
Varity_R		0.19
gMVP		0.39

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: rs782372258; hg19: chrX-100911751;