7-4781098-C-T

Position:

• chr7-4781098-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014855.3(AP5Z1):​c.42-77C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,537,422 control chromosomes in the GnomAD database, including 433 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: 33)
  • Exomes 𝑓: 0.021 (400 hom.)
• Consequence: AP5Z1 NM_014855.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0830

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-4781098-C-T is Benign according to our data. Variant chr7-4781098-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1207118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.016 (2436/152262) while in subpopulation SAS AF= 0.0253 (122/4828). AF 95% confidence interval is 0.0226. There are 33 homozygotes in gnomad4. There are 1152 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.42-77C>T		intron_variant		ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.-240-77C>T		intron_variant			NP_001351787.1
AP5Z1	NR_157345.1	n.135-77C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.42-77C>T		intron_variant			NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2436 AN: 152144 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.0212 AC: 29387 AN: 1385160 Hom.: 400 AF XY: 0.0215 AC XY: 14675 AN XY: 681068

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0320

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.00666

Gnomad4 NFE exome AF: 0.0228

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0160 AC: 2436 AN: 152262 Hom.: 33 Cov.: 33 AF XY: 0.0155 AC XY: 1152 AN XY: 74442

Gnomad4 AFR AF: 0.00426

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0197 Hom.: 2

Bravo AF: 0.0172

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs143180624; hg19: chr7-4820729;