chr15-89903965-T-G

Position:

• chr15-89903965-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182616.4(ARPIN):​c.320A>C​(p.Asp107Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,455,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ARPIN NM_182616.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

Genes affected

ARPIN (HGNC:28782): (actin related protein 2/3 complex inhibitor) Involved in directional locomotion; negative regulation of cell migration; and negative regulation of cellular component organization. Predicted to be located in lamellipodium. [provided by Alliance of Genome Resources, Apr 2022]

ARPIN-AP3S2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20420837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARPIN	NM_182616.4	c.320A>C	p.Asp107Ala	missense_variant	4/6	ENST00000357484.10
ARPIN-AP3S2	NM_001199058.2	c.320A>C	p.Asp107Ala	missense_variant	4/10
ARPIN	NM_001282380.2	c.32A>C	p.Asp11Ala	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARPIN	ENST00000357484.10	c.320A>C	p.Asp107Ala	missense_variant	4/6	1	NM_182616.4	P1
ARPIN	ENST00000460685.1	c.32A>C	p.Asp11Ala	missense_variant	4/6	2
ARPIN	ENST00000560096.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1455254 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 724058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000286 Hom.: 0

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

Dec 15, 2023

The c.320A>C (p.D107A) alteration is located in exon 4 (coding exon 4) of the ARPIN gene. This alteration results from a A to C substitution at nucleotide position 320, causing the aspartic acid (D) at amino acid position 107 to be replaced by an alanine (A). 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	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	.;.;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	.;.;M;.
MutationTaster	Benign	0.86	N;N;N
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Benign	0.041
Sift	Uncertain	0.010	D;D;T;T
Sift4G	Uncertain	0.013	D;.;T;T
Polyphen		0.45	.;.;P;.
Vest4		0.30
MVP		0.30
MPC		0.062
ClinPred		0.38	T
GERP RS		2.4
Varity_R		0.085
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1018377268; hg19: chr15-90447197;