Genetic Variant ARPC3:c.253-10_253-5dupTTTTTT (chr12-110436687-G-GAAAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001278556.2(ARPC3):c.253-10_253-5dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 806,810 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 0)

Exomes 𝑓: 0.000096 ( 1 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.253-10_253-5dupTTTTTT		splice_region intron	N/A	NP_001265485.1	O15145
	ARPC3	NM_001287222.2		c.253-10_253-5dupTTTTTT		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_253-4insTTTTTT	splice_region intron	N/A	ENSP00000228825.7	O15145
ARPC3	ENST00000888155.1		c.355-5_355-4insTTTTTT	splice_region intron	N/A	ENSP00000558214.1
ARPC3	ENST00000888156.1		c.313-5_313-4insTTTTTT	splice_region intron	N/A	ENSP00000558215.1

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

350

AN:

85606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00291

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:

0.000244

Gnomad OTH

AF:

0.00278

GnomAD4 exome

AF:

0.0000957

AC:

AN:

721176

Hom.:

Cov.:

AF XY:

0.0000961

AC XY:

AN XY:

374756

show subpopulations

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

African (AFR)

AF:

0.00216

AC:

AN:

12978

American (AMR)

AF:

0.000178

AC:

AN:

33646

Ashkenazi Jewish (ASJ)

AF:

0.000131

AC:

AN:

15312

East Asian (EAS)

AF:

0.00

AC:

AN:

24338

South Asian (SAS)

AF:

0.00

AC:

AN:

55176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2800

European-Non Finnish (NFE)

AF:

0.0000487

AC:

AN:

513144

Other (OTH)

AF:

0.000255

AC:

AN:

31370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00410

AC:

351

AN:

85634

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

135

AN XY:

39986

show subpopulations

African (AFR)

AF:

0.0128

AC:

316

AN:

24600

American (AMR)

AF:

0.00291

AC:

AN:

7570

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:

0.000244

AC:

AN:

40932

Other (OTH)

AF:

0.00277

AC:

AN:

1084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Mutation Taster

=97/3

polymorphism

(source)

Splicing

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

Publications

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12-110436687-GA-GAAAAAAA

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