rs141754568

Positions:

chr7-100105959-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_004722.4(AP4M1):c.930G>A(p.Arg310Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000616 in 1,614,142 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 10 hom. )

Consequence

AP4M1
NM_004722.4 splice_region, synonymous

Scores

Splicing: ADA: 0.02884

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-100105959-G-A is Benign according to our data. Variant chr7-100105959-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218652.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr7-100105959-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=3.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000644 (98/152270) while in subpopulation SAS AF= 0.00228 (11/4830). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4M1	NM_004722.4 link	c.930G>A	p.Arg310Arg	splice_region_variant, synonymous_variant	12/15	ENST00000359593.9	NP_004713.2	O00189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9 link	c.930G>A	p.Arg310Arg	splice_region_variant, synonymous_variant	12/15	1	NM_004722.4	ENSP00000352603.4		O00189

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000736

AC:

185

AN:

251490

Hom.:

AF XY:

0.000883

AC XY:

120

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00216

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.000272

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000613

AC:

896

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

496

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.000824

Gnomad4 NFE exome

AF:

0.000342

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.000644

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000658

Hom.:

Bravo

AF:

0.000491

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 28, 2022

- -

AP4M1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

AP4M1: BP4, BP7 -

Hereditary spastic paraplegia 50

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.029

dbscSNV1_RF

Benign

0.22

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