NM_005720.4:c.314C>T

Variant names:

• chr7-99388183-C-T
• rs1186149065
• NM_005720.4:c.314C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_005720.4(ARPC1B):​c.314C>T​(p.Ala105Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ARPC1B NM_005720.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90
• Publications: 4 publications found

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]

ARPC1B Gene-Disease associations (from GenCC):

• platelet abnormalities with eosinophilia and immune-mediated inflammatory disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000284292 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-99388183-C-T is Pathogenic according to our data. Variant chr7-99388183-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 444878.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARPC1B	NM_005720.4	c.314C>T	p.Ala105Val	missense_variant	Exon 4 of 10	ENST00000646101.2	NP_005711.1
ARPC1B	XM_024446628.2	c.314C>T	p.Ala105Val	missense_variant	Exon 4 of 10		XP_024302396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARPC1B	ENST00000646101.2	c.314C>T	p.Ala105Val	missense_variant	Exon 4 of 10		NM_005720.4	ENSP00000496599.1
ENSG00000284292	ENST00000638617.1	c.1310C>T	p.Ala437Val	missense_variant	Exon 11 of 17	5		ENSP00000491073.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease Pathogenic:1

Aug 03, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.058	.;T;T;T;T;.;T;T;T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;.;.;.;D;.;.;.;.;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	.;.;L;L;L;.;L;L;L;L;L
PhyloP100		7.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	.;D;.;D;D;D;D;D;D;D;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	.;D;.;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	.;D;.;D;D;D;D;D;D;D;.
Polyphen		0.89	.;.;P;P;P;.;P;P;P;P;P
Vest4		0.47, 0.47
MutPred		0.68		.;Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);Gain of methylation at K110 (P = 0.0849);
MVP		0.82
MPC		0.50
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.74
gMVP		0.34
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1186149065; hg19: chr7-98985806;