3-35717327-A-G

Position:

• chr3-35717327-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001385562.1(ARPP21):​c.965A>G​(p.Asn322Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARPP21 NM_001385562.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044045657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPP21	NM_001385562.1	c.965A>G	p.Asn322Ser	missense_variant	13/21	ENST00000684406.1	NP_001372491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPP21	ENST00000684406.1	c.965A>G	p.Asn322Ser	missense_variant	13/21		NM_001385562.1	ENSP00000506922	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.965A>G (p.N322S) alteration is located in exon 13 (coding exon 11) of the ARPP21 gene. This alteration results from a A to G substitution at nucleotide position 965, causing the asparagine (N) at amino acid position 322 to be replaced by a serine (S). 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	Benign	0.054
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.30
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.084
Sift	Benign	0.85	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0	B;B
Vest4		0.15
MutPred		0.16		Gain of glycosylation at T324 (P = 0.0769);.;
MVP		0.12
ClinPred		0.50	D
GERP RS		4.2
Varity_R		0.044
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-35758819;