dbSNP rs184752711: AP5Z1:c.1708-5C>T (chr7-4789827-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014855.3(AP5Z1):c.1708-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,551,156 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 12 hom., cov: 32)

Exomes 𝑓: 0.014 ( 211 hom. )

Consequence

AP5Z1
NM_014855.3 splice_region, intron

Scores

Splicing: ADA: 0.00004138

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.434

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-4789827-C-T is Benign according to our data. Variant chr7-4789827-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0097 (1476/152190) while in subpopulation NFE AF = 0.0166 (1125/67976). AF 95% confidence interval is 0.0157. There are 12 homozygotes in GnomAd4. There are 650 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 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	Effect	Exon Rank	Protein	UniProt
AP5Z1	NM_014855.3	MANE Select	c.1708-5C>T	splice_region intron	N/A	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1		c.1240-5C>T	splice_region intron	N/A	NP_001351787.1
AP5Z1	NR_157345.1		n.1839-5C>T	splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AP5Z1	ENST00000649063.2	MANE Select	c.1708-5C>T	splice_region intron	N/A	ENSP00000497815.1	O43299-1
AP5Z1	ENST00000865634.1		c.1783-5C>T	splice_region intron	N/A	ENSP00000535693.1
AP5Z1	ENST00000865636.1		c.1777-5C>T	splice_region intron	N/A	ENSP00000535695.1

Frequencies

GnomAD3 genomes

AF:

0.00971

AC:

1477

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00295

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0166

Gnomad OTH

AF:

0.00767

GnomAD2 exomes

AF:

0.0104

AC:

1601

AN:

154540

AF XY:

0.0111

show subpopulations

Gnomad AFR exome

AF:

0.00224

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.00413

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00684

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0145

AC:

20284

AN:

1398966

Hom.:

211

Cov.:

AF XY:

0.0144

AC XY:

9962

AN XY:

690244

show subpopulations

African (AFR)

AF:

0.00199

AC:

AN:

31658

American (AMR)

AF:

0.00432

AC:

155

AN:

35880

Ashkenazi Jewish (ASJ)

AF:

0.00497

AC:

125

AN:

25144

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35842

South Asian (SAS)

AF:

0.0118

AC:

938

AN:

79264

European-Finnish (FIN)

AF:

0.00726

AC:

350

AN:

48206

Middle Eastern (MID)

AF:

0.00669

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0166

AC:

17917

AN:

1079278

Other (OTH)

AF:

0.0120

AC:

697

AN:

58010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1020

2041

3061

4082

5102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.00970

AC:

1476

AN:

152190

Hom.:

Cov.:

AF XY:

0.00874

AC XY:

650

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00294

AC:

122

AN:

41528

American (AMR)

AF:

0.00536

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.00891

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1125

AN:

67976

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0137

Hom.:

Bravo

AF:

0.00865

Asia WGS

AF:

0.00404

AC:

AN:

3478

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 specified (2)

Hereditary spastic paraplegia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.4

(source)

DANN

Benign

0.64

PhyloP100

-0.43

PromoterAI

0.090

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000041

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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