19-10581758-T-C

Position:

• chr19-10581758-T-C

Variant summary

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

The NM_005498.5(AP1M2):​c.388A>G​(p.Ile130Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AP1M2 NM_005498.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

Genes affected

AP1M2 (HGNC:558): (adaptor related protein complex 1 subunit mu 2) This gene encodes a subunit of the heterotetrameric adaptor-related protein comlex 1 (AP-1), which belongs to the adaptor complexes medium subunits family. This protein is capable of interacting with tyrosine-based sorting signals. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1M2	NM_005498.5	c.388A>G	p.Ile130Val	missense_variant	4/12	ENST00000250244.11	NP_005489.2
AP1M2	NM_001300887.2	c.388A>G	p.Ile130Val	missense_variant	4/12		NP_001287816.1
AP1M2	XM_047438018.1	c.310A>G	p.Ile104Val	missense_variant	4/12		XP_047293974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1M2	ENST00000250244.11	c.388A>G	p.Ile130Val	missense_variant	4/12	1	NM_005498.5	ENSP00000250244.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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 30, 2024

The c.388A>G (p.I130V) alteration is located in exon 4 (coding exon 4) of the AP1M2 gene. This alteration results from a A to G substitution at nucleotide position 388, causing the isoleucine (I) at amino acid position 130 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	.;T;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L;L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.86	.;N;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.24	.;T;.;.;.
Sift4G	Benign	0.41	T;T;.;.;T
Polyphen		0.13	B;P;.;.;.
Vest4		0.44
MutPred		0.37		Gain of methylation at K129 (P = 0.0426);Gain of methylation at K129 (P = 0.0426);.;.;.;
MVP		0.64
MPC		0.18
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.18
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 1

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: chr19-10692434;