7-100101724-C-T

Position:

chr7-100101724-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_004722.4(AP4M1):c.10C>T(p.Gln4Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000188 in 1,599,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AP4M1
NM_004722.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.30

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:

MCM7 (HGNC:6950): (minichromosome maintenance complex component 7) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. The MCM complex consisting of this protein and MCM2, 4 and 6 proteins possesses DNA helicase activity, and may act as a DNA unwinding enzyme. Cyclin D1-dependent kinase, CDK4, is found to associate with this protein, and may regulate the binding of this protein with the tumorsuppressor protein RB1/RB. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

MCM7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-100101724-C-T is Pathogenic according to our data. Variant chr7-100101724-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4M1	NM_004722.4 linkuse as main transcript	c.10C>T	p.Gln4Ter	stop_gained	1/15	ENST00000359593.9	NP_004713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9 linkuse as main transcript	c.10C>T	p.Gln4Ter	stop_gained	1/15	1	NM_004722.4	ENSP00000352603	P3

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250908

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449252

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720668

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000667

AC:

AN:

149912

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73166

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 50

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 04, 2022	This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 33813722). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 981454). This variant is present in population databases (rs777220438, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln4*) in the AP4M1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4M1 are known to be pathogenic (PMID: 24700674, 25496299, 25558065). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 19, 2021

PVS1, PM2 -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A;A;D;D

Vest4

0.21, 0.17

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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