Genetic Variant NM_005498.5:c.1121C>A (chr19-10574956-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005498.5(AP1M2):c.1121C>A(p.Pro374His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,593,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

AP1M2
NM_005498.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.81

Publications

0 publications found

Variant links:

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]

AP1M2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.1121C>A	p.Pro374His	missense	Exon 10 of 12	NP_005489.2
	AP1M2	NM_001300887.2		c.1127C>A	p.Pro376His	missense	Exon 10 of 12	NP_001287816.1	Q9Y6Q5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP1M2	ENST00000250244.11	TSL:1 MANE Select	c.1121C>A	p.Pro374His	missense	Exon 10 of 12	ENSP00000250244.5	Q9Y6Q5-1
AP1M2	ENST00000590923.5	TSL:1	c.1127C>A	p.Pro376His	missense	Exon 10 of 12	ENSP00000465685.1	Q9Y6Q5-2
AP1M2	ENST00000918520.1		c.1115C>A	p.Pro372His	missense	Exon 10 of 12	ENSP00000588579.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000844

AC:

AN:

225044

AF XY:

0.0000735

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000189

Gnomad ASJ exome

AF:

0.00101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000996

Gnomad OTH exome

AF:

0.000371

GnomAD4 exome

AF:

0.0000250

AC:

AN:

1441148

Hom.:

Cov.:

AF XY:

0.0000266

AC XY:

AN XY:

714888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32726

American (AMR)

AF:

0.000141

AC:

AN:

42422

Ashkenazi Jewish (ASJ)

AF:

0.000675

AC:

AN:

25202

East Asian (EAS)

AF:

0.00

AC:

AN:

38670

South Asian (SAS)

AF:

0.0000358

AC:

AN:

83876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00000454

AC:

AN:

1100448

Other (OTH)

AF:

0.0000841

AC:

AN:

59452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41384

American (AMR)

AF:

0.0000656

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000879

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000497

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

4.0

PhyloP100

9.8

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.43

Sift

Uncertain

0.016

Sift4G

Uncertain

0.014

Polyphen

0.97

Vest4

0.81

MutPred

0.69

Loss of catalytic residue at P374 (P = 0.0069)

MVP

0.64

MPC

0.69

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.56

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over