chr7-99386688-T-C

Position:

• chr7-99386688-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005720.4(ARPC1B):​c.68T>C​(p.Ile23Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARPC1B NM_005720.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

ARPC1B (HGNC:704): (actin related protein 2/3 complex subunit 1B) This gene encodes one of seven subunits of the human Arp2/3 protein complex. This subunit is a member of the SOP2 family of proteins and is most similar to the protein encoded by gene ARPC1A. The similarity between these two proteins suggests that they both may function as p41 subunit of the human Arp2/3 complex that has been implicated in the control of actin polymerization in cells. It is possible that the p41 subunit is involved in assembling and maintaining the structure of the Arp2/3 complex. Multiple versions of the p41 subunit may adapt the functions of the complex to different cell types or developmental stages. This protein also has a role in centrosomal homeostasis by being an activator and substrate of the Aurora A kinase. [provided by RefSeq, Mar 2011]

ENSG00000284292 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPC1B	NM_005720.4	c.68T>C	p.Ile23Thr	missense_variant	3/10	ENST00000646101.2	NP_005711.1
ARPC1B	XM_024446628.2	c.68T>C	p.Ile23Thr	missense_variant	3/10		XP_024302396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPC1B	ENST00000646101.2	c.68T>C	p.Ile23Thr	missense_variant	3/10		NM_005720.4	ENSP00000496599.1
ENSG00000284292	ENST00000638617.1	c.1064T>C	p.Ile355Thr	missense_variant	10/17	5		ENSP00000491073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461144 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726936

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2025

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 23 of the ARPC1B protein (p.Ile23Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARPC1B-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ARPC1B protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.;T;T;T;.;.;.;T;T;T;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;.;.;.;D;D;D;.;.;.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.7	.;.;.;M;M;M;.;.;.;M;M;M;M;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	.;D;D;.;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	.;D;D;.;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.0070	.;D;D;.;D;D;D;.;D;D;D;D;D;.
Polyphen		0.99	.;.;.;D;D;D;.;.;.;D;D;D;D;D
Vest4		0.84, 0.84
MVP		0.89
MPC		0.64
ClinPred		0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1460142998; hg19: chr7-98984311;