NM_005498.5:c.1043T>C

Variant names:

• chr19-10577202-A-G
• rs1917263252
• NM_005498.5:c.1043T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005498.5(AP1M2):​c.1043T>C​(p.Phe348Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AP1M2 NM_005498.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

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.1043T>C	p.Phe348Ser	missense	Exon 9 of 12	NP_005489.2
	AP1M2	NM_001300887.2		c.1049T>C	p.Phe350Ser	missense	Exon 9 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.1043T>C	p.Phe348Ser	missense	Exon 9 of 12	ENSP00000250244.5	Q9Y6Q5-1
	AP1M2	ENST00000590923.5	TSL:1	c.1049T>C	p.Phe350Ser	missense	Exon 9 of 12	ENSP00000465685.1	Q9Y6Q5-2
	AP1M2	ENST00000918520.1		c.1037T>C	p.Phe346Ser	missense	Exon 9 of 12	ENSP00000588579.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456752 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724422

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109858

Other (OTH) AF: 0.00 AC: 0 AN: 60100

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.00061	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.55	P
Vest4		0.62
MutPred		0.82		Gain of disorder (P = 0.0089)
MVP		0.40
MPC		0.35
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.75
Mutation Taster		=60/40	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: rs1917263252; hg19: chr19-10687878;