rs73305371

Variant names:

• chr7-4783682-A-G
• rs73305371
• NM_014855.3:c.512-7A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-4783682-A-G
• chr7-4783682-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014855.3(AP5Z1):​c.512-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,548,868 control chromosomes in the GnomAD database, including 2,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1481 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1377 hom.)
• Consequence: AP5Z1 NM_014855.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003628
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.57
• Publications: 4 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=-0.88).
• BP6: Variant 7-4783682-A-G is Benign according to our data. Variant chr7-4783682-A-G is described in ClinVar as Benign. ClinVar VariationId is 360312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 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.512-7A>G		splice_region intron	N/A	NP_055670.1
	AP5Z1	NM_001364858.1		c.44-7A>G		splice_region intron	N/A	NP_001351787.1
	AP5Z1	NR_157345.1		n.605-7A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.512-7A>G		splice_region intron	N/A	ENSP00000497815.1
	AP5Z1	ENST00000865634.1		c.512-7A>G		splice_region intron	N/A	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.512-7A>G		splice_region intron	N/A	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.0797 AC: 12123 AN: 152098 Hom.: 1475 Cov.: 33

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.0675

GnomAD2 exomes AF: 0.0191 AC: 2945 AN: 154268 AF XY: 0.0156

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000539

Gnomad NFE exome AF: 0.00710

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0137 AC: 19151 AN: 1396654 Hom.: 1377 Cov.: 32 AF XY: 0.0125 AC XY: 8631 AN XY: 688626

African (AFR) AF: 0.282 AC: 8907 AN: 31532

American (AMR) AF: 0.0191 AC: 679 AN: 35602

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 93 AN: 25090

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35684

South Asian (SAS) AF: 0.00124 AC: 98 AN: 79168

European-Finnish (FIN) AF: 0.000663 AC: 32 AN: 48300

Middle Eastern (MID) AF: 0.0109 AC: 62 AN: 5684

European-Non Finnish (NFE) AF: 0.00731 AC: 7881 AN: 1077686

Other (OTH) AF: 0.0241 AC: 1398 AN: 57908

GnomAD4 genome AF: 0.0798 AC: 12148 AN: 152214 Hom.: 1481 Cov.: 33 AF XY: 0.0760 AC XY: 5655 AN XY: 74424

African (AFR) AF: 0.265 AC: 11002 AN: 41530

American (AMR) AF: 0.0320 AC: 490 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00663 AC: 451 AN: 67982

Other (OTH) AF: 0.0668 AC: 141 AN: 2112

Alfa AF: 0.0280 Hom.: 211

Bravo AF: 0.0921

Asia WGS AF: 0.0140 AC: 49 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	-0.88
CADD	Benign	0.22
DANN	Benign	0.38
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.070		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: rs73305371; hg19: chr7-4823313;