7-99385765-C-G

Position:

• chr7-99385765-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_005720.4(ARPC1B):​c.51C>G​(p.Asn17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,610,334 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (3 hom.)
• Consequence: ARPC1B NM_005720.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.22

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.397295).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000985 (15/152342) while in subpopulation SAS AF= 0.000414 (2/4828). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPC1B	NM_005720.4	c.51C>G	p.Asn17Lys	missense_variant	2/10	ENST00000646101.2	NP_005711.1
ARPC1B	XM_024446628.2	c.51C>G	p.Asn17Lys	missense_variant	2/10		XP_024302396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPC1B	ENST00000646101.2	c.51C>G	p.Asn17Lys	missense_variant	2/10		NM_005720.4	ENSP00000496599	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152224 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 60 AN: 241936 Hom.: 1 AF XY: 0.000290 AC XY: 38 AN XY: 131014

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00109

Gnomad FIN exome AF: 0.000103

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1457992 Hom.: 3 Cov.: 31 AF XY: 0.000236 AC XY: 171 AN XY: 724960

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: 0.000996

Gnomad4 FIN exome AF: 0.0000577

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152342 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74482

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 17 of the ARPC1B protein (p.Asn17Lys). This variant is present in population databases (rs142972568, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ARPC1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1464016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARPC1B protein function. 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	1.0
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	.;T;.;T;T;T;.;T;.;T;T;T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D;D;.;.;.;D;D;D;.;.;.;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	.;.;.;M;M;M;.;.;.;M;M;M;M;M
MutationTaster	Benign	1.0	N;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.4	.;D;D;.;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	.;D;D;.;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.0030	.;D;D;.;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	.;.;.;D;D;D;.;.;.;D;D;D;D;D
Vest4		0.93
MutPred		0.72		.;Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);Gain of methylation at N17 (P = 0.0225);
MVP		0.70
MPC		1.3
ClinPred		0.40	T
GERP RS		1.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.73

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: rs142972568; hg19: chr7-98983388;