chr7-4784252-CG-AA

Variant names:

• chr7-4784252-CG-AA
• NM_014855.3:c.671_672delCGinsAA
• AP5Z1 p.Thr224Lys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014855.3(AP5Z1):​c.671_672delCGinsAA​(p.Thr224Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T224M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• Publications: 0 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	NM_014855.3	MANE Select	c.671_672delCGinsAA	p.Thr224Lys	missense	N/A	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.203_204delCGinsAA	p.Thr68Lys	missense	N/A	NP_001351787.1
	AP5Z1	NR_157345.1		n.764_765delCGinsAA		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.671_672delCGinsAA	p.Thr224Lys	missense	N/A	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.671_672delCGinsAA	p.Thr224Lys	missense	N/A	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.671_672delCGinsAA	p.Thr224Lys	missense	N/A	ENSP00000535695.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-4823883;