15-89908307-T-G

Position:

• chr15-89908307-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182616.4(ARPIN):​c.274A>C​(p.Asn92His) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARPIN NM_182616.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.65

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:38824): (ARPIN-AP3S2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring C15orf38 (chromosome 15 open reading frame 38) and AP3S2 (adaptor-related protein complex 3, sigma 2 subunit) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPIN	NM_182616.4	c.274A>C	p.Asn92His	missense_variant	3/6	ENST00000357484.10	NP_872422.1
ARPIN-AP3S2	NM_001199058.2	c.274A>C	p.Asn92His	missense_variant	3/10		NP_001185987.1
ARPIN	NM_001282380.2	c.-15A>C		5_prime_UTR_variant	3/6		NP_001269309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPIN	ENST00000357484.10	c.274A>C	p.Asn92His	missense_variant	3/6	1	NM_182616.4	ENSP00000350075.5
ARPIN-AP3S2	ENST00000398333.7	c.274A>C	p.Asn92His	missense_variant	3/10	2		ENSP00000381377.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Jul 27, 2024

The c.274A>C (p.N92H) alteration is located in exon 3 (coding exon 3) of the ARPIN gene. This alteration results from a A to C substitution at nucleotide position 274, causing the asparagine (N) at amino acid position 92 to be replaced by a histidine (H). 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	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	0.038
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.5	.;M
PROVEAN	Benign	-2.1	N;D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	.;D
Vest4		0.68
MutPred		0.88		Loss of ubiquitination at K90 (P = 0.0587);Loss of ubiquitination at K90 (P = 0.0587);
MVP		0.35
MPC		0.21
ClinPred		0.92	D
GERP RS		3.0
Varity_R		0.17
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr15-90451539;