rs193920911

Variant names:

• chr3-35729432-G-T
• rs193920911
• NM_001385562.1:c.1355G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001385562.1(ARPP21):​c.1355G>T​(p.Gly452Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARPP21 NM_001385562.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.32
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385562.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPP21	NM_001385562.1	MANE Select	c.1355G>T	p.Gly452Val	missense	Exon 15 of 21	NP_001372491.1
	ARPP21	NM_001385595.1		c.1358G>T	p.Gly453Val	missense	Exon 15 of 21	NP_001372524.1
	ARPP21	NM_001385490.1		c.1355G>T	p.Gly452Val	missense	Exon 15 of 21	NP_001372419.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPP21	ENST00000684406.1	MANE Select	c.1355G>T	p.Gly452Val	missense	Exon 15 of 21	ENSP00000506922.1
	ARPP21	ENST00000187397.8	TSL:1	c.1355G>T	p.Gly452Val	missense	Exon 15 of 20	ENSP00000187397.4
	ARPP21	ENST00000444190.5	TSL:1	c.1193G>T	p.Gly398Val	missense	Exon 13 of 19	ENSP00000405276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.84
MutPred		0.41		Gain of sheet (P = 0.0344)
MVP		0.28
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.67
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs193920911; hg19: chr3-35770924; COSMIC: COSV51805004; COSMIC: COSV51805004;