Genetic Variant AP4M1:p.Leu334Leu (chr7-100106268-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004722.4(AP4M1):c.1002C>T(p.Leu334Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,614,108 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 23 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 207 hom. )

Consequence

AP4M1
NM_004722.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.598

Variant links:

Genes affected

AP4M1 (HGNC:574): (adaptor related protein complex 4 subunit mu 1) This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]

AP4M1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 7-100106268-C-T is Benign according to our data. Variant chr7-100106268-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100106268-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.598 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4M1	NM_004722.4 link	c.1002C>T	p.Leu334Leu	synonymous_variant	Exon 13 of 15	ENST00000359593.9	NP_004713.2	O00189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9 link	c.1002C>T	p.Leu334Leu	synonymous_variant	Exon 13 of 15	1	NM_004722.4	ENSP00000352603.4		O00189

Frequencies

GnomAD3 genomes

AF:

0.00681

AC:

1036

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00551

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.0170

AC:

4275

AN:

251132

Hom.:

150

AF XY:

0.0148

AC XY:

2004

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.0833

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00947

Gnomad FIN exome

AF:

0.00610

Gnomad NFE exome

AF:

0.00752

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.00853

AC:

12466

AN:

1461780

Hom.:

207

Cov.:

AF XY:

0.00820

AC XY:

5963

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.0758

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00934

Gnomad4 FIN exome

AF:

0.00684

Gnomad4 NFE exome

AF:

0.00656

Gnomad4 OTH exome

AF:

0.00831

GnomAD4 genome

AF:

0.00680

AC:

1036

AN:

152328

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

480

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.0295

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00766

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.00551

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.0107

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 28, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 50

Benign:2

Dec 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Oct 07, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.0

DANN

Benign

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over