rs199653684

Variant names:

• chr19-10574483-T-G
• rs199653684
• NM_005498.5:c.1183A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005498.5(AP1M2):​c.1183A>C​(p.Met395Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,564,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AP1M2 NM_005498.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055730164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005498.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1M2	NM_005498.5	MANE Select	c.1183A>C	p.Met395Leu	missense	Exon 11 of 12	NP_005489.2
	AP1M2	NM_001300887.2		c.1189A>C	p.Met397Leu	missense	Exon 11 of 12	NP_001287816.1	Q9Y6Q5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1M2	ENST00000250244.11	TSL:1 MANE Select	c.1183A>C	p.Met395Leu	missense	Exon 11 of 12	ENSP00000250244.5	Q9Y6Q5-1
	AP1M2	ENST00000590923.5	TSL:1	c.1189A>C	p.Met397Leu	missense	Exon 11 of 12	ENSP00000465685.1	Q9Y6Q5-2
	AP1M2	ENST00000918520.1		c.1177A>C	p.Met393Leu	missense	Exon 11 of 12	ENSP00000588579.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000851 AC: 15 AN: 176360 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000191

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.000115 AC: 163 AN: 1412204 Hom.: 0 Cov.: 30 AF XY: 0.000112 AC XY: 78 AN XY: 697706

African (AFR) AF: 0.00 AC: 0 AN: 32230

American (AMR) AF: 0.0000271 AC: 1 AN: 36964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25312

East Asian (EAS) AF: 0.00 AC: 0 AN: 37146

South Asian (SAS) AF: 0.00 AC: 0 AN: 79996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5272

European-Non Finnish (NFE) AF: 0.000143 AC: 155 AN: 1086320

Other (OTH) AF: 0.000119 AC: 7 AN: 58660

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.0000425 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.57
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-2.9	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.6	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.69		Loss of MoRF binding (P = 0.0794)
MVP		0.088
MPC		0.14
ClinPred		0.25	T
GERP RS		5.4
Varity_R		0.28
gMVP		0.32
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199653684; hg19: chr19-10685159;