Genetic Variant AP5M1:p.Val6Met (chr14-57269330-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_018229.4(AP5M1):c.16G>A(p.Val6Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,122 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V6L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0095 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 35 hom. )

Consequence

AP5M1
NM_018229.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.534

Publications

0 publications found

Variant links:

Genes affected

AP5M1 (HGNC:20192): (adaptor related protein complex 5 subunit mu 1) Involved in endosomal transport. Located in several cellular components, including cytosol; late endosome; and lysosome. Part of AP-type membrane coat adaptor complex. [provided by Alliance of Genome Resources, Apr 2022]

AP5M1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055793524).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00948 (1443/152272) while in subpopulation AFR AF = 0.0335 (1392/41542). AF 95% confidence interval is 0.032. There are 24 homozygotes in GnomAd4. There are 673 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5M1	NM_018229.4 link	c.16G>A	p.Val6Met	missense_variant	Exon 1 of 8	ENST00000261558.8	NP_060699.3	Q9H0R1-1A0A024R654
AP5M1	XM_011536940.4 link	c.16G>A	p.Val6Met	missense_variant	Exon 1 of 9		XP_011535242.1	E7EQ45
AP5M1	NR_026895.2 link	n.360G>A		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5M1	ENST00000261558.8 link	c.16G>A	p.Val6Met	missense_variant	Exon 1 of 8	1	NM_018229.4	ENSP00000261558.3		Q9H0R1-1
AP5M1	ENST00000431972.6 link	c.16G>A	p.Val6Met	missense_variant	Exon 1 of 9	2		ENSP00000390531.2		E7EQ45

Frequencies

GnomAD3 genomes

AF:

0.00948

AC:

1443

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00245

AC:

615

AN:

251410

AF XY:

0.00177

show subpopulations

Gnomad AFR exome

AF:

0.0352

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00101

AC:

1478

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000890

AC XY:

647

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0389

AC:

1301

AN:

33472

American (AMR)

AF:

0.00114

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111990

Other (OTH)

AF:

0.00166

AC:

100

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

142

212

283

354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00948

AC:

1443

AN:

152272

Hom.:

Cov.:

AF XY:

0.00904

AC XY:

673

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0335

AC:

1392

AN:

41542

American (AMR)

AF:

0.00209

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68014

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

136

205

273

341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00373

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0356

AC:

157

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00301

AC:

366

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0048

T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PhyloP100

0.53

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.039

Sift

Benign

0.039

D;T

Sift4G

Uncertain

0.032

D;D

Polyphen

0.0030

B;.

Vest4

0.16

MVP

0.44

MPC

0.11

ClinPred

0.038

GERP RS

1.6

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.050

gMVP

0.41

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over