7-99385775-A-G

Position:

• chr7-99385775-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005720.4(ARPC1B):​c.61A>G​(p.Thr21Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARPC1B NM_005720.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPC1B	NM_005720.4	c.61A>G	p.Thr21Ala	missense_variant	2/10	ENST00000646101.2	NP_005711.1
ARPC1B	XM_024446628.2	c.61A>G	p.Thr21Ala	missense_variant	2/10		XP_024302396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPC1B	ENST00000646101.2	c.61A>G	p.Thr21Ala	missense_variant	2/10		NM_005720.4	ENSP00000496599	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456626 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724168

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jul 06, 2022

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. Experimental studies have shown that this missense change affects ARPC1B function (PMID: 20603326). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1467855). This variant has not been reported in the literature in individuals affected with ARPC1B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 21 of the ARPC1B protein (p.Thr21Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0098	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	.;T;.;T;T;T;.;T;.;T;T;T;T;T
Eigen	Benign	0.087
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;.;.;.;D;D;D;.;.;.;.;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	.;.;.;M;M;M;.;.;.;M;M;M;M;M
MutationTaster	Benign	0.99	N;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	.;D;D;.;D;D;D;D;D;D;D;D;D;.
REVEL	Benign	0.24
Sift	Benign	0.031	.;D;D;.;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.011	.;D;D;.;D;D;D;D;D;D;D;D;D;.
Polyphen		0.59	.;.;.;P;P;P;.;.;.;P;P;P;P;P
Vest4		0.40, 0.40
MutPred		0.46		.;Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);Loss of ubiquitination at K18 (P = 0.0992);
MVP		0.73
MPC		0.41
ClinPred		0.97	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-98983398;