rs73305392

Variant names:

• chr7-4790664-C-T
• rs73305392
• NM_014855.3:c.1939-9C>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.1939-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,611,958 control chromosomes in the GnomAD database, including 778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (383 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (395 hom.)
• Consequence: AP5Z1 NM_014855.3 intron
• Scores: Splicing: ADA: 0.000001825
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.467
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 7-4790664-C-T is Benign according to our data. Variant chr7-4790664-C-T is described in ClinVar as Benign. ClinVar VariationId is 360341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 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.1939-9C>T		intron	N/A	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.1471-9C>T		intron	N/A	NP_001351787.1
	AP5Z1	NR_157345.1		n.2070-9C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.1939-9C>T		intron	N/A	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.2014-9C>T		intron	N/A	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.2008-9C>T		intron	N/A	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6316 AN: 152132 Hom.: 383 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0129 AC: 3169 AN: 245626 AF XY: 0.0105

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.00323

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000618

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.00873

GnomAD4 exome AF: 0.00929 AC: 13561 AN: 1459708 Hom.: 395 Cov.: 32 AF XY: 0.00849 AC XY: 6163 AN XY: 726118

African (AFR) AF: 0.142 AC: 4764 AN: 33466

American (AMR) AF: 0.00852 AC: 380 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 85 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00106 AC: 91 AN: 86208

European-Finnish (FIN) AF: 0.000693 AC: 36 AN: 51968

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.00660 AC: 7332 AN: 1111574

Other (OTH) AF: 0.0138 AC: 830 AN: 60318

GnomAD4 genome AF: 0.0415 AC: 6325 AN: 152250 Hom.: 383 Cov.: 33 AF XY: 0.0400 AC XY: 2976 AN XY: 74460

African (AFR) AF: 0.133 AC: 5512 AN: 41538

American (AMR) AF: 0.0175 AC: 268 AN: 15290

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00625 AC: 425 AN: 68012

Other (OTH) AF: 0.0284 AC: 60 AN: 2110

Alfa AF: 0.0419 Hom.: 245

Bravo AF: 0.0468

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00636

ClinVar

ClinVar submissions

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	-0.61
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000018
dbscSNV1_RF	Benign	0.028
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: rs73305392; hg19: chr7-4830295;