rs41280965

chr7-100102755-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004722.4(AP4M1):c.228C>T(p.Pro76=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00705 in 1,614,124 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0071 (65 hom.)
• Consequence: AP4M1 NM_004722.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-100102755-C-T is Benign according to our data. Variant chr7-100102755-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100102755-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00628 (956/152284) while in subpopulation NFE AF= 0.00863 (587/68016). AF 95% confidence interval is 0.00805. There are 6 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4M1	NM_004722.4	c.228C>T	p.Pro76=	synonymous_variant	3/15	ENST00000359593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4M1	ENST00000359593.9	c.228C>T	p.Pro76=	synonymous_variant	3/15	1	NM_004722.4	P3

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 956 AN: 152166 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00863

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00729 AC: 1832 AN: 251464 Hom.: 11 AF XY: 0.00723 AC XY: 982 AN XY: 135916

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00926

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00714 AC: 10431 AN: 1461840 Hom.: 65 Cov.: 33 AF XY: 0.00712 AC XY: 5175 AN XY: 727230

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.0160

Gnomad4 NFE exome AF: 0.00732

Gnomad4 OTH exome AF: 0.00710

GnomAD4 genome AF: 0.00628 AC: 956 AN: 152284 Hom.: 6 Cov.: 31 AF XY: 0.00633 AC XY: 471 AN XY: 74452

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00863

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00871 Hom.: 4

Bravo AF: 0.00531

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2016	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. -

Hereditary spastic paraplegia 50 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 17, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

AP4M1: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.1
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs41280965; hg19: chr7-99700378; COSMIC: COSV57996466; COSMIC: COSV57996466;