chr15-89903870-C-T

Position:

• chr15-89903870-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182616.4(ARPIN):​c.415G>A​(p.Ala139Thr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A139V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARPIN NM_182616.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARPIN	NM_182616.4	c.415G>A	p.Ala139Thr	missense_variant	4/6	ENST00000357484.10
ARPIN-AP3S2	NM_001199058.2	c.415G>A	p.Ala139Thr	missense_variant	4/10
ARPIN	NM_001282380.2	c.127G>A	p.Ala43Thr	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARPIN	ENST00000357484.10	c.415G>A	p.Ala139Thr	missense_variant	4/6	1	NM_182616.4	P1
ARPIN	ENST00000560096.1	c.76G>A	p.Ala26Thr	missense_variant	1/2	2
ARPIN	ENST00000460685.1	c.127G>A	p.Ala43Thr	missense_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jan 16, 2024

The c.415G>A (p.A139T) alteration is located in exon 4 (coding exon 4) of the ARPIN gene. This alteration results from a G to A substitution at nucleotide position 415, causing the alanine (A) at amino acid position 139 to be replaced by a threonine (T). 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	0.30
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	.;.;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.6	.;.;M;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D;D;T;D
Sift4G	Uncertain	0.0050	D;.;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.81
MutPred		0.78		Gain of glycosylation at A139 (P = 0.0269);.;Gain of glycosylation at A139 (P = 0.0269);.;
MVP		0.48
MPC		0.34
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.14
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr15-90447102;