NM_014855.3:c.2278_2280dupATG

Variant names:

• chr7-4791237-A-AGAT
• rs1554259059
• NM_014855.3:c.2278_2280dupATG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_014855.3(AP5Z1):​c.2278_2280dupATG​(p.Met760dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P761P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP5Z1 NM_014855.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_014855.3. Strenght limited to Supporting due to length of the change: 1aa.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	NM_014855.3	MANE Select	c.2278_2280dupATG	p.Met760dup	conservative_inframe_insertion	Exon 17 of 17	NP_055670.1
	AP5Z1	NM_001364858.1		c.1810_1812dupATG	p.Met604dup	conservative_inframe_insertion	Exon 16 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.2409_2411dupATG		non_coding_transcript_exon	Exon 17 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.2278_2280dupATG	p.Met760dup	conservative_inframe_insertion	Exon 17 of 17	ENSP00000497815.1
	AP5Z1	ENST00000865634.1		c.2353_2355dupATG	p.Met785dup	conservative_inframe_insertion	Exon 18 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.2347_2349dupATG	p.Met783dup	conservative_inframe_insertion	Exon 17 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

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

Other links and lift over

dbSNP: rs1554259059; hg19: chr7-4830868;