rs201687417

Variant names:

• chr7-4788256-A-G
• rs201687417
• NM_014855.3:c.1557A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-4788256-A-G
• chr7-4788256-A-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014855.3(AP5Z1):​c.1557A>G​(p.Gln519Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,589,082 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: AP5Z1 NM_014855.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.586
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-4788256-A-G is Benign according to our data. Variant chr7-4788256-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360332.
• BP7: Synonymous conserved (PhyloP=0.586 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00314 (477/151976) while in subpopulation AFR AF = 0.0105 (436/41466). AF 95% confidence interval is 0.0097. There are 3 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	NM_014855.3	MANE Select	c.1557A>G	p.Gln519Gln	synonymous	Exon 12 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.1089A>G	p.Gln363Gln	synonymous	Exon 11 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.1688A>G		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.1557A>G	p.Gln519Gln	synonymous	Exon 12 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.1557A>G	p.Gln519Gln	synonymous	Exon 12 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.1626A>G	p.Gln542Gln	synonymous	Exon 12 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 474 AN: 151858 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000718 AC: 149 AN: 207574 AF XY: 0.000592

Gnomad AFR exome AF: 0.00826

Gnomad AMR exome AF: 0.000820

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.000956

GnomAD4 exome AF: 0.000484 AC: 696 AN: 1437106 Hom.: 7 Cov.: 31 AF XY: 0.000459 AC XY: 327 AN XY: 712782

African (AFR) AF: 0.0127 AC: 418 AN: 33020

American (AMR) AF: 0.00101 AC: 42 AN: 41390

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38548

South Asian (SAS) AF: 0.0000970 AC: 8 AN: 82498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50614

Middle Eastern (MID) AF: 0.00283 AC: 13 AN: 4596

European-Non Finnish (NFE) AF: 0.000130 AC: 143 AN: 1101390

Other (OTH) AF: 0.00120 AC: 71 AN: 59374

GnomAD4 genome AF: 0.00314 AC: 477 AN: 151976 Hom.: 3 Cov.: 32 AF XY: 0.00299 AC XY: 222 AN XY: 74326

African (AFR) AF: 0.0105 AC: 436 AN: 41466

American (AMR) AF: 0.00131 AC: 20 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67938

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00382

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Hereditary spastic paraplegia 48 (2)
-	1	-	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.70
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs201687417; hg19: chr7-4827887;