chr7-4777125-C-G

Variant names:

• chr7-4777125-C-G
• rs17135110
• NM_014855.3:c.41+1369C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014855.3(AP5Z1):​c.41+1369C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 152,224 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.061 (353 hom., cov: 32)
• Consequence: AP5Z1 NM_014855.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.306
• Publications: 5 publications found

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]

AP5Z1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 48

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.41+1369C>G		intron_variant	Intron 1 of 16	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.-241+1369C>G		intron_variant	Intron 1 of 15		NP_001351787.1
AP5Z1	NR_157345.1	n.134+1369C>G		intron_variant	Intron 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.41+1369C>G		intron_variant	Intron 1 of 16		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 9251 AN: 152106 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0444

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0615

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0607

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0609 AC: 9269 AN: 152224 Hom.: 353 Cov.: 32 AF XY: 0.0619 AC XY: 4603 AN XY: 74420

African (AFR) AF: 0.0452 AC: 1879 AN: 41544

American (AMR) AF: 0.0442 AC: 676 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3470

East Asian (EAS) AF: 0.0614 AC: 318 AN: 5178

South Asian (SAS) AF: 0.187 AC: 904 AN: 4822

European-Finnish (FIN) AF: 0.0402 AC: 426 AN: 10596

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0641 AC: 4358 AN: 68012

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0619 Hom.: 34

Bravo AF: 0.0562

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.73
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17135110; hg19: chr7-4816756;