rs397704705

Variant names:

• chr7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA
• rs397704705
• NM_014855.3:c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_014855.3(AP5Z1):​c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA​(p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn) variant causes a stop gained, missense, disruptive inframe insertion change. 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP5Z1 NM_014855.3 stop_gained, missense, disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.67
• Publications: 2 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: Pathogenic. The variant received 16 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 55 pathogenic variants in the truncated region.
• PP5: Variant 7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA is Pathogenic according to our data. Variant chr7-4781213-GGAT-TGCTGTAAACTGTAACTGTAAA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained missense disruptive_inframe_insertion	Exon 2 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.-202_-199delGGATinsTGCTGTAAACTGTAACTGTAAA		5_prime_UTR	Exon 2 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.173_176delGGATinsTGCTGTAAACTGTAACTGTAAA		non_coding_transcript_exon	Exon 2 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained missense disruptive_inframe_insertion	Exon 2 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained missense disruptive_inframe_insertion	Exon 2 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.80_83delGGATinsTGCTGTAAACTGTAACTGTAAA	p.Arg27_Ile28delinsLeuLeuTerThrValThrValAsn	stop_gained missense disruptive_inframe_insertion	Exon 2 of 17	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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary spastic paraplegia 48 (2)
1	-	-	Macular dystrophy with or without extraocular features (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

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

Other links and lift over

dbSNP: rs397704705; hg19: chr7-4820844;