Genetic Variant ARPC3:c.253-11_253-5dupTTTTTTT (chr12-110436687-G-GAAAAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001278556.2(ARPC3):c.253-11_253-5dupTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 807,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

ARPC3
NM_001278556.2 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.29

Publications

2 publications found

Variant links:

Genes affected

ARPC3 (HGNC:706): (actin related protein 2/3 complex subunit 3) This gene encodes one of seven subunits of the human Arp2/3 protein complex. The Arp2/3 protein complex has been conserved through evolution and is implicated in the control of actin polymerization in cells. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]

ARPC3 links:

ENSG00000258210 (HGNC:):

ENSG00000258210 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278556.2. 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
	ARPC3	NM_001278556.2	MANE Select	c.253-11_253-5dupTTTTTTT		splice_region intron	N/A	NP_001265485.1	O15145
	ARPC3	NM_001287222.2		c.253-11_253-5dupTTTTTTT		splice_region intron	N/A	NP_001274151.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARPC3	ENST00000228825.12	TSL:1 MANE Select	c.253-5_253-4insTTTTTTT	splice_region intron	N/A	ENSP00000228825.7	O15145
ARPC3	ENST00000888155.1		c.355-5_355-4insTTTTTTT	splice_region intron	N/A	ENSP00000558214.1
ARPC3	ENST00000888156.1		c.313-5_313-4insTTTTTTT	splice_region intron	N/A	ENSP00000558215.1

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

85726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000970

AC:

AN:

721284

Hom.:

Cov.:

AF XY:

0.00000534

AC XY:

AN XY:

374800

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000768

AC:

AN:

13026

American (AMR)

AF:

0.00

AC:

AN:

33660

Ashkenazi Jewish (ASJ)

AF:

0.0000653

AC:

AN:

15316

East Asian (EAS)

AF:

0.00

AC:

AN:

24338

South Asian (SAS)

AF:

0.00

AC:

AN:

55170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2802

European-Non Finnish (NFE)

AF:

0.00000974

AC:

AN:

513170

Other (OTH)

AF:

0.00

AC:

AN:

31390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000320446), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.304

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000466

AC:

AN:

85752

Hom.:

Cov.:

AF XY:

0.0000500

AC XY:

AN XY:

40034

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000162

AC:

AN:

24712

American (AMR)

AF:

0.00

AC:

AN:

7578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2206

East Asian (EAS)

AF:

0.00

AC:

AN:

2500

South Asian (SAS)

AF:

0.00

AC:

AN:

2550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

40930

Other (OTH)

AF:

0.00

AC:

AN:

1084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0261725), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-110436687-GA-GAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over