rs146682319

Variant names:

• chr7-4781259-C-T
• rs146682319
• NM_014855.3:c.126C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-4781259-C-T
• chr7-4781259-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001364858.1(AP5Z1):​c.-156C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,613,848 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: AP5Z1 NM_001364858.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.30
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-4781259-C-T is Benign according to our data. Variant chr7-4781259-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446846.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00297 (452/152316) while in subpopulation AFR AF = 0.0103 (427/41574). AF 95% confidence interval is 0.00947. There are 1 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364858.1. 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.126C>T	p.Leu42Leu	synonymous	Exon 2 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.-156C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001351787.1
	AP5Z1	NM_001364858.1		c.-156C>T		5_prime_UTR	Exon 2 of 16	NP_001351787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.126C>T	p.Leu42Leu	synonymous	Exon 2 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.126C>T	p.Leu42Leu	synonymous	Exon 2 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.126C>T	p.Leu42Leu	synonymous	Exon 2 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000947 AC: 236 AN: 249192 AF XY: 0.000777

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000316 AC: 462 AN: 1461532 Hom.: 3 Cov.: 31 AF XY: 0.000294 AC XY: 214 AN XY: 727046

African (AFR) AF: 0.00959 AC: 321 AN: 33478

American (AMR) AF: 0.000805 AC: 36 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111790

Other (OTH) AF: 0.000712 AC: 43 AN: 60360

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74476

African (AFR) AF: 0.0103 AC: 427 AN: 41574

American (AMR) AF: 0.000654 AC: 10 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00357

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spastic paraplegia 48 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.047
DANN	Benign	0.56
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs146682319; hg19: chr7-4820890; COSMIC: COSV104664028; COSMIC: COSV104664028;