7-4784903-C-T

Variant names:

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.791-5C>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 0.00119 in 1,607,180 control chromosomes in the GnomAD database, including 17 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 0.0056 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 8 hom. )

Consequence

AP5Z1
NM_014855.3 splice_region, intron

Scores

Splicing: ADA: 0.00001958

Clinical Significance

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

Conservation

PhyloP100: -0.540

Publications

3 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

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=-0.81).

BP6

Variant 7-4784903-C-T is Benign according to our data. Variant chr7-4784903-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00557 (849/152326) while in subpopulation AFR AF = 0.0194 (806/41592). AF 95% confidence interval is 0.0183. There are 9 homozygotes in GnomAd4. There are 387 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3 link	c.791-5C>T	splice_region_variant, intron_variant	Intron 6 of 16	ENST00000649063.2	NP_055670.1	O43299-1
AP5Z1	NM_001364858.1 link	c.323-5C>T	splice_region_variant, intron_variant	Intron 5 of 15		NP_001351787.1
AP5Z1	NR_157345.1 link	n.884-5C>T	splice_region_variant, intron_variant	Intron 6 of 16
AP5Z1	XM_047421098.1 link	c.455-5C>T	splice_region_variant, intron_variant	Intron 4 of 14		XP_047277054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2 link	c.791-5C>T		splice_region_variant, intron_variant	Intron 6 of 16		NM_014855.3	ENSP00000497815.1		O43299-1

Frequencies

GnomAD3 genomes

AF:

0.00557

AC:

848

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00146

AC:

349

AN:

239632

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.000587

Gnomad ASJ exome

AF:

0.00225

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000188

Gnomad OTH exome

AF:

0.000847

GnomAD4 exome

AF:

0.000735

AC:

1069

AN:

1454854

Hom.:

Cov.:

AF XY:

0.000678

AC XY:

490

AN XY:

722680

show subpopulations

African (AFR)

AF:

0.0218

AC:

728

AN:

33334

American (AMR)

AF:

0.000743

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00257

AC:

AN:

26022

East Asian (EAS)

AF:

0.000101

AC:

AN:

39426

South Asian (SAS)

AF:

0.000140

AC:

AN:

85806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52140

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000113

AC:

125

AN:

1107956

Other (OTH)

AF:

0.00160

AC:

AN:

59996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00557

AC:

849

AN:

152326

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

387

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0194

AC:

806

AN:

41592

American (AMR)

AF:

0.00137

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68014

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00339

Hom.:

Bravo

AF:

0.00647

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 15, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia 48

Benign:2

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Mar 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.57

(source)

DANN

Benign

0.46

PhyloP100

-0.54

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over