rs201478168

Variant names:

• chr7-4790794-C-G
• rs201478168
• NM_014855.3:c.2060C>G
• AP5Z1 p.Ser687Cys

Your query was ambiguous. Multiple possible variants found:

• chr7-4790794-C-G
• chr7-4790794-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014855.3(AP5Z1):​c.2060C>G​(p.Ser687Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000901 in 1,609,144 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S687S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (1 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.50
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2060C>G	p.Ser687Cys	missense	Exon 16 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.1592C>G	p.Ser531Cys	missense	Exon 15 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.2191C>G		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.2060C>G	p.Ser687Cys	missense	Exon 16 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.2135C>G	p.Ser712Cys	missense	Exon 17 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.2129C>G	p.Ser710Cys	missense	Exon 16 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000791 AC: 19 AN: 240350 AF XY: 0.0000610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000165

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000892 AC: 130 AN: 1456954 Hom.: 1 Cov.: 32 AF XY: 0.0000745 AC XY: 54 AN XY: 724466

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000113 AC: 126 AN: 1110856

Other (OTH) AF: 0.0000664 AC: 4 AN: 60234

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.42	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Benign	0.049	D
Sift4G	Uncertain	0.025	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.27
Mutation Taster		=84/16	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201478168;

hg19: chr7-4830425;