7-4788844-G-T

Position:

• chr7-4788844-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_014855.3(AP5Z1):​c.1600G>T​(p.Ala534Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,605,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A534V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0230

Genes affected

AP5Z1 (HGNC:22197): (adaptor related protein complex 5 subunit zeta 1) This gene was identified by genome-wide screen for genes involved in homologous recombination DNA double-strand break repair (HR-DSBR). The encoded protein was found in a complex with other proteins that have a role in HR-DSBR. Knockdown of this gene reduced homologous recombination, and mutations in this gene were found in patients with spastic paraplegia. It was concluded that this gene likely encodes a helicase (PMID:20613862). [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004574567).
• BP6: Variant 7-4788844-G-T is Benign according to our data. Variant chr7-4788844-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210221.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP5Z1	NM_014855.3	c.1600G>T	p.Ala534Ser	missense_variant	13/17	ENST00000649063.2
AP5Z1	NM_001364858.1	c.1132G>T	p.Ala378Ser	missense_variant	12/16
AP5Z1	XM_047421098.1	c.1264G>T	p.Ala422Ser	missense_variant	11/15
AP5Z1	NR_157345.1	n.1731G>T		non_coding_transcript_exon_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1600G>T	p.Ala534Ser	missense_variant	13/17		NM_014855.3	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000240 AC: 56 AN: 233302 Hom.: 0 AF XY: 0.000211 AC XY: 27 AN XY: 128248

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00488

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000869

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000120 AC: 175 AN: 1453078 Hom.: 0 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 722436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000316

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2020	- -

Hereditary spastic paraplegia 48 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.4
DANN	Benign	0.66
DEOGEN2	Benign	0.0091	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.61	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.36	N;.
REVEL	Benign	0.032
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0070	B;B
Vest4		0.21
MVP		0.014
ClinPred		0.020	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.099

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs372517211; hg19: chr7-4828475; COSMIC: COSV105267234; COSMIC: COSV105267234;