rs111358719

Variant names:

• chr7-4787691-C-T
• rs111358719
• NM_014855.3:c.1369C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014855.3(AP5Z1):​c.1369C>T​(p.Leu457Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0027 in 1,551,994 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: AP5Z1 NM_014855.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.73
• 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-4787691-C-T is Benign according to our data. Variant chr7-4787691-C-T is described in ClinVar as Benign. ClinVar VariationId is 360329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2121/152268) while in subpopulation AFR AF = 0.0481 (1997/41548). AF 95% confidence interval is 0.0463. There are 48 homozygotes in GnomAd4. There are 1040 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 AR gene

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.1369C>T	p.Leu457Leu	synonymous	Exon 11 of 17	NP_055670.1
	AP5Z1	NM_001364858.1		c.901C>T	p.Leu301Leu	synonymous	Exon 10 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.1500C>T		non_coding_transcript_exon	Exon 11 of 17

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.1369C>T	p.Leu457Leu	synonymous	Exon 11 of 17	ENSP00000497815.1
	AP5Z1	ENST00000650581.1		c.169C>T	p.Leu57Leu	synonymous	Exon 2 of 7	ENSP00000497156.1
	AP5Z1	ENST00000477454.1	TSL:4	n.150C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2116 AN: 152150 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00337 AC: 529 AN: 157008 AF XY: 0.00252

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000272

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00148 AC: 2070 AN: 1399726 Hom.: 42 Cov.: 31 AF XY: 0.00126 AC XY: 871 AN XY: 690948

African (AFR) AF: 0.0501 AC: 1591 AN: 31760

American (AMR) AF: 0.00299 AC: 108 AN: 36108

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35984

South Asian (SAS) AF: 0.000176 AC: 14 AN: 79376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46930

Middle Eastern (MID) AF: 0.00290 AC: 16 AN: 5516

European-Non Finnish (NFE) AF: 0.000147 AC: 159 AN: 1080740

Other (OTH) AF: 0.00310 AC: 180 AN: 58112

GnomAD4 genome AF: 0.0139 AC: 2121 AN: 152268 Hom.: 48 Cov.: 32 AF XY: 0.0140 AC XY: 1040 AN XY: 74456

African (AFR) AF: 0.0481 AC: 1997 AN: 41548

American (AMR) AF: 0.00490 AC: 75 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68004

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00553 Hom.: 9

Bravo AF: 0.0152

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.6
DANN	Benign	0.56
PhyloP100		3.7
Mutation Taster		=97/3	polymorphism

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: rs111358719; hg19: chr7-4827322;