7-4788253-C-T

Variant names:

• chr7-4788253-C-T
• rs77560694
• NM_014855.3:c.1554C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014855.3(AP5Z1):​c.1554C>T​(p.Phe518Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,588,518 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (134 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (110 hom.)
• Consequence: AP5Z1 NM_014855.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.984
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 7-4788253-C-T is Benign according to our data. Variant chr7-4788253-C-T is described in ClinVar as Benign. ClinVar VariationId is 240936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.984 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

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.1554C>T	p.Phe518Phe	synonymous	Exon 12 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.1086C>T	p.Phe362Phe	synonymous	Exon 11 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.1685C>T		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.1554C>T	p.Phe518Phe	synonymous	Exon 12 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.1554C>T	p.Phe518Phe	synonymous	Exon 12 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.1623C>T	p.Phe541Phe	synonymous	Exon 12 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3445 AN: 152120 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00532 AC: 1096 AN: 206084 AF XY: 0.00421

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000541

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00254 AC: 3645 AN: 1436280 Hom.: 110 Cov.: 31 AF XY: 0.00221 AC XY: 1573 AN XY: 712270

African (AFR) AF: 0.0808 AC: 2664 AN: 32978

American (AMR) AF: 0.00472 AC: 195 AN: 41272

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25656

East Asian (EAS) AF: 0.00 AC: 0 AN: 38506

South Asian (SAS) AF: 0.0000971 AC: 8 AN: 82406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50592

Middle Eastern (MID) AF: 0.00565 AC: 26 AN: 4598

European-Non Finnish (NFE) AF: 0.000393 AC: 433 AN: 1100930

Other (OTH) AF: 0.00533 AC: 316 AN: 59342

GnomAD4 genome AF: 0.0226 AC: 3445 AN: 152238 Hom.: 134 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74440

African (AFR) AF: 0.0785 AC: 3259 AN: 41532

American (AMR) AF: 0.00745 AC: 114 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68012

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.00811 Hom.: 19

Bravo AF: 0.0255

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 48 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.4
DANN	Benign	0.69
PhyloP100		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs77560694; hg19: chr7-4827884;