Genetic Variant ARPP21:p.Leu330Leu (chr3-35717352-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001385517.1(ARPP21):c.779C>G(p.Ser260Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,597,296 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 19 hom. )

Consequence

ARPP21
NM_001385517.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.675

Variant links:

Genes affected

ARPP21 (HGNC:16968): (cAMP regulated phosphoprotein 21) This gene encodes a cAMP-regulated phosphoprotein. The encoded protein is enriched in the caudate nucleus and cerebellar cortex. A similar protein in mouse may be involved in regulating the effects of dopamine in the basal ganglia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ARPP21 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 3-35717352-C-G is Benign according to our data. Variant chr3-35717352-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2653652.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARPP21	NM_001385562.1 link	c.990C>G	p.Leu330Leu	synonymous_variant	Exon 13 of 21	ENST00000684406.1	NP_001372491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARPP21	ENST00000684406.1 link	c.990C>G	p.Leu330Leu	synonymous_variant	Exon 13 of 21		NM_001385562.1	ENSP00000506922.1		A0A804HI65

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

456

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00377

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00294

AC:

737

AN:

250924

Hom.:

AF XY:

0.00273

AC XY:

371

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.0126

Gnomad NFE exome

AF:

0.00310

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00236

AC:

3418

AN:

1445242

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1702

AN XY:

720362

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00292

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000419

Gnomad4 FIN exome

AF:

0.0122

Gnomad4 NFE exome

AF:

0.00228

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00300

AC:

456

AN:

152054

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

249

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.00223

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.00377

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00358

Hom.:

Bravo

AF:

0.00166

EpiCase

AF:

0.00213

EpiControl

AF:

0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARPP21: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

9.9

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over