7-99353989-T-C

Variant names:

• chr7-99353989-T-C
• rs150009166
• NM_006409.4:c.581T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006409.4(ARPC1A):​c.581T>C​(p.Leu194Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: ARPC1A NM_006409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

Genes affected

ARPC1A (HGNC:703): (actin related protein 2/3 complex subunit 1A) 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 ARPC1B. 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ENSG00000284292 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3086037).
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARPC1A	NM_006409.4	c.581T>C	p.Leu194Pro	missense_variant	Exon 6 of 10	ENST00000262942.10	NP_006400.2
ARPC1A	NM_001190996.2	c.539T>C	p.Leu180Pro	missense_variant	Exon 6 of 10		NP_001177925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARPC1A	ENST00000262942.10	c.581T>C	p.Leu194Pro	missense_variant	Exon 6 of 10	1	NM_006409.4	ENSP00000262942.5
ENSG00000284292	ENST00000638617.1	c.581T>C	p.Leu194Pro	missense_variant	Exon 6 of 17	5		ENSP00000491073.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152216 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000406 AC: 102 AN: 251228 Hom.: 0 AF XY: 0.000479 AC XY: 65 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000449 AC: 656 AN: 1461686 Hom.: 1 Cov.: 30 AF XY: 0.000455 AC XY: 331 AN XY: 727158

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000487

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152334 Hom.: 0 Cov.: 31 AF XY: 0.000174 AC XY: 13 AN XY: 74510

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000654

EpiControl AF: 0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.581T>C (p.L194P) alteration is located in exon 6 (coding exon 5) of the ARPC1A gene. This alteration results from a T to C substitution at nucleotide position 581, causing the leucine (L) at amino acid position 194 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.4	.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	.;D
Sift4G	Benign	0.14	.;T
Polyphen		0.73	.;P
Vest4		0.71
MVP		0.53
MPC		1.3
ClinPred		0.13	T
GERP RS		5.0
Varity_R		0.95
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs150009166; hg19: chr7-98951612;