Genetic Variant AP5Z1:p.Glu399Glu (chr7-4786314-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014855.3(AP5Z1):c.1197G>A(p.Glu399Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,613,778 control chromosomes in the GnomAD database, including 450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 32)

Exomes 𝑓: 0.021 ( 417 hom. )

Consequence

AP5Z1
NM_014855.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.76

Publications

5 publications found

Variant links:

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

AP5Z1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 7-4786314-G-A is Benign according to our data. Variant chr7-4786314-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.76 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0159 (2425/152328) while in subpopulation SAS AF = 0.0249 (120/4824). AF 95% confidence interval is 0.0224. There are 33 homozygotes in GnomAd4. There are 1148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5Z1	NM_014855.3	MANE Select	c.1197G>A	p.Glu399Glu	synonymous	Exon 10 of 17	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1		c.729G>A	p.Glu243Glu	synonymous	Exon 9 of 16	NP_001351787.1
AP5Z1	NR_157345.1		n.1290G>A		non_coding_transcript_exon	Exon 10 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP5Z1	ENST00000649063.2	MANE Select	c.1197G>A	p.Glu399Glu	synonymous	Exon 10 of 17	ENSP00000497815.1	O43299-1
AP5Z1	ENST00000865634.1		c.1197G>A	p.Glu399Glu	synonymous	Exon 10 of 18	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.1197G>A	p.Glu399Glu	synonymous	Exon 10 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2425

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00424

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0249

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0234

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0174

AC:

4339

AN:

248912

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0334

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00641

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0212

AC:

30926

AN:

1461450

Hom.:

417

Cov.:

AF XY:

0.0215

AC XY:

15613

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00373

AC:

125

AN:

33478

American (AMR)

AF:

0.0150

AC:

672

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

846

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0229

AC:

1972

AN:

86250

European-Finnish (FIN)

AF:

0.00685

AC:

365

AN:

53306

Middle Eastern (MID)

AF:

0.0486

AC:

280

AN:

5764

European-Non Finnish (NFE)

AF:

0.0227

AC:

25246

AN:

1111772

Other (OTH)

AF:

0.0235

AC:

1420

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1696

3392

5088

6784

8480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

954

1908

2862

3816

4770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0159

AC:

2425

AN:

152328

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1148

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00426

AC:

177

AN:

41588

American (AMR)

AF:

0.0179

AC:

274

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0249

AC:

120

AN:

4824

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0234

AC:

1591

AN:

68018

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

129

258

386

515

644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0214

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0274

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 48 (2)

not provided (2)

not specified (2)

Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.43

(source)

DANN

Benign

0.68

PhyloP100

1.8

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over