X-101625113-A-T

Variant names:

• chrX-101625113-A-T
• rs782644531
• NM_177947.3:c.134A>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_177947.3(ARMCX3):​c.134A>T​(p.Asp45Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000133 in 1,201,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 6 hem.)
• Consequence: ARMCX3 NM_177947.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

Genes affected

ARMCX3 (HGNC:24065): (armadillo repeat containing X-linked 3) This gene encodes a member of the ALEX family of proteins which may play a role in tumor suppression. The encoded protein contains a potential N-terminal transmembrane domain and a single Armadillo (arm) repeat. Other proteins containing the arm repeat are involved in development, maintenance of tissue integrity, and tumorigenesis. This gene is closely localized with other family members on the X chromosome. Three transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.101041526).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMCX3	NM_177947.3	c.134A>T	p.Asp45Val	missense_variant	Exon 5 of 5	ENST00000471229.7	NP_808816.1
ARMCX3	NM_016607.4	c.134A>T	p.Asp45Val	missense_variant	Exon 5 of 5		NP_057691.1
ARMCX3	NM_177948.3	c.134A>T	p.Asp45Val	missense_variant	Exon 5 of 5		NP_808817.1
ARMCX3	XM_005262141.4	c.134A>T	p.Asp45Val	missense_variant	Exon 5 of 5		XP_005262198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMCX3	ENST00000471229.7	c.134A>T	p.Asp45Val	missense_variant	Exon 5 of 5	1	NM_177947.3	ENSP00000454483.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111905 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34083

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000653 AC: 11 AN: 168424 Hom.: 0 AF XY: 0.0000550 AC XY: 3 AN XY: 54548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000757

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 14 AN: 1089212 Hom.: 0 Cov.: 31 AF XY: 0.0000168 AC XY: 6 AN XY: 356098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000399

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111957 Hom.: 0 Cov.: 23 AF XY: 0.0000586 AC XY: 2 AN XY: 34145

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000565

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134A>T (p.D45V) alteration is located in exon 5 (coding exon 1) of the ARMCX3 gene. This alteration results from a A to T substitution at nucleotide position 134, causing the aspartic acid (D) at amino acid position 45 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;T;T;.;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.77	.;.;T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.;.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.43	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.18	T;T;D;D;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.43	B;B;.;.;B
Vest4		0.31
MutPred		0.31		Loss of solvent accessibility (P = 0.0544);Loss of solvent accessibility (P = 0.0544);Loss of solvent accessibility (P = 0.0544);Loss of solvent accessibility (P = 0.0544);Loss of solvent accessibility (P = 0.0544);
MVP		0.92
MPC		1.5
ClinPred		0.073	T
GERP RS		4.4
Varity_R		0.21
gMVP		0.54

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: rs782644531; hg19: chrX-100880103;