rs201862383

Variant names:

• chr7-4784252-C-T
• rs201862383
• NM_014855.3:c.671C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-4784252-C-T
• chr7-4784252-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_014855.3(AP5Z1):​c.671C>T​(p.Thr224Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,590,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T224T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.46
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

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.671C>T	p.Thr224Met	missense	Exon 6 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.203C>T	p.Thr68Met	missense	Exon 5 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.764C>T		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.671C>T	p.Thr224Met	missense	Exon 6 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.671C>T	p.Thr224Met	missense	Exon 6 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.671C>T	p.Thr224Met	missense	Exon 6 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000166 AC: 36 AN: 217478 AF XY: 0.000202

Gnomad AFR exome AF: 0.0000823

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000626

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000135 AC: 194 AN: 1438642 Hom.: 0 Cov.: 39 AF XY: 0.000141 AC XY: 101 AN XY: 714218

African (AFR) AF: 0.000121 AC: 4 AN: 32978

American (AMR) AF: 0.0000238 AC: 1 AN: 41988

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25432

East Asian (EAS) AF: 0.00 AC: 0 AN: 38414

South Asian (SAS) AF: 0.000421 AC: 35 AN: 83106

European-Finnish (FIN) AF: 0.000180 AC: 9 AN: 49882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000121 AC: 133 AN: 1101792

Other (OTH) AF: 0.000185 AC: 11 AN: 59336

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151994 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74224

African (AFR) AF: 0.000121 AC: 5 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4784

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.000166 AC: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Hereditary spastic paraplegia 48 (2)
-	1	-	High myopia (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.31
ClinPred		0.81	D
GERP RS		4.3
Varity_R		0.66
gMVP		0.77
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs201862383; hg19: chr7-4823883;