7-100106268-C-T

Position:

• chr7-100106268-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000359593.9(AP4M1):​c.1002C>T​(p.Leu334=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L334L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (207 hom.)
• Consequence: AP4M1 ENST00000359593.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.598

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=-0.53).
• 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/exons	MANE	Protein	UniProt
AP4M1	NM_004722.4	c.1002C>T	p.Leu334=	synonymous_variant	13/15	ENST00000359593.9	NP_004713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9	c.1002C>T	p.Leu334=	synonymous_variant	13/15	1	NM_004722.4	ENSP00000352603	P3

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 1036 AN: 152210 Hom.: 22 Cov.: 32

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

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.: 33 AF XY: 0.00820 AC XY: 5963 AN XY: 727196

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.: 23 Cov.: 32 AF XY: 0.00644 AC XY: 480 AN XY: 74488

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.: 3

Bravo AF: 0.0107

Asia WGS AF: 0.00375 AC: 13 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

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2017	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 13, 2021	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Other links and lift over

dbSNP: rs140843407; hg19: chr7-99703891;