rs999885

chr7-100103553-G-Achr7-100103553-G-Cchr7-100103553-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004722.4(AP4M1):c.462+34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,518 control chromosomes in the GnomAD database, including 229,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18579 hom., cov: 31)
  • Exomes 𝑓: 0.53 (210588 hom.)
• Consequence: AP4M1 NM_004722.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.532

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-100103553-G-A is Benign according to our data. Variant chr7-100103553-G-A is described in ClinVar as [Benign]. Clinvar id is 678005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4M1	NM_004722.4	c.462+34G>A		intron_variant		ENST00000359593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4M1	ENST00000359593.9	c.462+34G>A		intron_variant		1	NM_004722.4	P3

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72051 AN: 151894 Hom.: 18569 Cov.: 31

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.505

GnomAD3 exomes AF: 0.558 AC: 140229 AN: 251472 Hom.: 40835 AF XY: 0.563 AC XY: 76563 AN XY: 135906

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.614

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.835

Gnomad SAS exome AF: 0.639

Gnomad FIN exome AF: 0.538

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.531 AC: 776684 AN: 1461506 Hom.: 210588 Cov.: 38 AF XY: 0.536 AC XY: 389706 AN XY: 727098

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.611

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.823

Gnomad4 SAS exome AF: 0.641

Gnomad4 FIN exome AF: 0.532

Gnomad4 NFE exome AF: 0.515

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome AF: 0.474 AC: 72094 AN: 152012 Hom.: 18579 Cov.: 31 AF XY: 0.484 AC XY: 35976 AN XY: 74298

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.571

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.541

Gnomad4 NFE AF: 0.515

Gnomad4 OTH AF: 0.509

Alfa AF: 0.514 Hom.: 8763

Bravo AF: 0.470

Asia WGS AF: 0.713 AC: 2481 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 50 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.1
Dann	Benign	0.37

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

LitVar

Other links and lift over

dbSNP: rs999885; hg19: chr7-99701176;