3-9793140-C-G

Variant names:

• chr3-9793140-C-G
• rs931589854
• NM_005718.5:c.3+16C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001198780.3(ARPC4):​c.19C>G​(p.Pro7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000576 in 1,388,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: ARPC4 NM_001198780.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 0 publications found

Genes affected

ARPC4 (HGNC:707): (actin related protein 2/3 complex subunit 4) This gene encodes one of seven subunits of the human Arp2/3 protein complex. This complex controls actin polymerization in cells and has been conserved throughout eukaryotic evolution. This gene encodes the p20 subunit, which is necessary for actin nucleation and high-affinity binding to F-actin. Alternative splicing results in multiple transcript variants. Naturally occurring read-through transcription exists between this gene and the downstream tubulin tyrosine ligase-like family, member 3 (TTLL3), which results in the production of a fusion protein. [provided by RefSeq, Nov 2010]

ARPC4-TTLL3 (HGNC:38830): (ARPC4-TTLL3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ARPC4 (actin related protein 2/3 complex, subunit 4) and TTLL3 (tubulin tyrosine ligase-like family, member 3) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

TADA3 (HGNC:19422): (transcriptional adaptor 3) DNA-binding transcriptional activator proteins increase the rate of transcription by interacting with the transcriptional machinery bound to the basal promoter in conjunction with adaptor proteins, possibly by acetylation and destabilization of nucleosomes. The protein encoded by this gene is a transcriptional activator adaptor and a component of the histone acetyl transferase (HAT) coactivator complex which plays a crucial role in chromatin modulation and cell cycle progression. Along with the other components of the complex, this protein links transcriptional activators bound to specific promoters, to histone acetylation and the transcriptional machinery. The protein is also involved in the stabilization and activation of the p53 tumor suppressor protein that plays a role in the cellular response to DNA damage. Alternate splicing results in multiple transcript variants of this gene. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07151592).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198780.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPC4	NM_005718.5	MANE Select	c.3+16C>G		intron	N/A	NP_005709.1	P59998-1
	ARPC4	NM_001198780.3		c.19C>G	p.Pro7Ala	missense	Exon 1 of 6	NP_001185709.1	P59998-3
	ARPC4-TTLL3	NM_001198793.1		c.3+16C>G		intron	N/A	NP_001185722.1	A0A0A6YYG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPC4	ENST00000397261.8	TSL:1 MANE Select	c.3+16C>G		intron	N/A	ENSP00000380431.2	P59998-1
	ARPC4-TTLL3	ENST00000397256.5	TSL:5	c.3+16C>G		intron	N/A	ENSP00000380427.1
	ARPC4	ENST00000433034.1	TSL:3	c.19C>G	p.Pro7Ala	missense	Exon 1 of 6	ENSP00000388169.1	P59998-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000576 AC: 8 AN: 1388822 Hom.: 0 Cov.: 32 AF XY: 0.00000438 AC XY: 3 AN XY: 684300

African (AFR) AF: 0.00 AC: 0 AN: 31168

American (AMR) AF: 0.00 AC: 0 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24914

East Asian (EAS) AF: 0.00 AC: 0 AN: 35370

South Asian (SAS) AF: 0.00 AC: 0 AN: 78938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00000652 AC: 7 AN: 1073946

Other (OTH) AF: 0.0000174 AC: 1 AN: 57576

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.5
DANN	Benign	0.94
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.10
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.023
Sift	Uncertain	0.029	D
Sift4G	Benign	0.084	T
Vest4		0.22
MutPred		0.10		Loss of glycosylation at P7 (P = 0.0192)
MVP		0.15
MPC		1.0
ClinPred		0.11	T
GERP RS		3.3
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.065
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs931589854; hg19: chr3-9834824;