1-183627576-C-T

Variant names:

• chr1-183627576-C-T
• rs202196300
• NM_005717.4:c.412G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005717.4(ARPC5):​c.412G>A​(p.Val138Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARPC5 NM_005717.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

ARPC5 (HGNC:708): (actin related protein 2/3 complex subunit 5) This gene encodes one of seven subunits of the human Arp2/3 protein complex. The Arp2/3 protein complex has been implicated in the control of actin polymerization in cells and has been conserved through evolution. The exact role of the protein encoded by this gene, the p16 subunit, has yet to be determined. Alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3748467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARPC5	NM_005717.4	c.412G>A	p.Val138Ile	missense_variant	Exon 4 of 4	ENST00000359856.11	NP_005708.1
ARPC5	NM_001270439.2	c.421G>A	p.Val141Ile	missense_variant	Exon 4 of 4		NP_001257368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARPC5	ENST00000359856.11	c.412G>A	p.Val138Ile	missense_variant	Exon 4 of 4	1	NM_005717.4	ENSP00000352918.6
ARPC5	ENST00000294742.6	c.421G>A	p.Val141Ile	missense_variant	Exon 4 of 4	1		ENSP00000294742.6
ARPC5	ENST00000367534.5	c.393+2885G>A		intron_variant	Intron 3 of 3	3		ENSP00000356504.1
ARPC5	ENST00000462965.1	n.1073G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461744 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412G>A (p.V138I) alteration is located in exon 4 (coding exon 4) of the ARPC5 gene. This alteration results from a G to A substitution at nucleotide position 412, causing the valine (V) at amino acid position 138 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	0.090
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.15
Sift	Benign	0.12	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.012	B;.
Vest4		0.35
MutPred		0.51		Loss of MoRF binding (P = 0.105);.;
MVP		0.34
MPC		1.2
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.23

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: rs202196300; hg19: chr1-183596711;