chr7-4790832-G-A

Variant names:

• chr7-4790832-G-A
• rs11766611
• NM_014855.3:c.2098G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014855.3(AP5Z1):​c.2098G>A​(p.Val700Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,609,232 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (25 hom., cov: 33)
  • Exomes 𝑓: 0.022 (407 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.51
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005810648).
• BP6: Variant 7-4790832-G-A is Benign according to our data. Variant chr7-4790832-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128411.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 = 0.017 (2584/152266) while in subpopulation NFE AF = 0.0257 (1750/67994). AF 95% confidence interval is 0.0247. There are 25 homozygotes in GnomAd4. There are 1215 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	NM_014855.3	MANE Select	c.2098G>A	p.Val700Met	missense	Exon 16 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.1630G>A	p.Val544Met	missense	Exon 15 of 16	NP_001351787.1
	AP5Z1	NR_157345.1		n.2229G>A		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.2098G>A	p.Val700Met	missense	Exon 16 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.2173G>A	p.Val725Met	missense	Exon 17 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.2167G>A	p.Val723Met	missense	Exon 16 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2583 AN: 152148 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0167 AC: 4026 AN: 240454 AF XY: 0.0169

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00599

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0254

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0222 AC: 32387 AN: 1456966 Hom.: 407 Cov.: 32 AF XY: 0.0217 AC XY: 15694 AN XY: 724336

African (AFR) AF: 0.00374 AC: 125 AN: 33396

American (AMR) AF: 0.0132 AC: 584 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00741 AC: 192 AN: 25924

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39626

South Asian (SAS) AF: 0.00281 AC: 240 AN: 85260

European-Finnish (FIN) AF: 0.0290 AC: 1495 AN: 51570

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5764

European-Non Finnish (NFE) AF: 0.0257 AC: 28503 AN: 1110808

Other (OTH) AF: 0.0194 AC: 1172 AN: 60262

GnomAD4 genome AF: 0.0170 AC: 2584 AN: 152266 Hom.: 25 Cov.: 33 AF XY: 0.0163 AC XY: 1215 AN XY: 74446

African (AFR) AF: 0.00433 AC: 180 AN: 41568

American (AMR) AF: 0.0156 AC: 238 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.0299 AC: 318 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0257 AC: 1750 AN: 67994

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.0189 Hom.: 45

Bravo AF: 0.0149

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00318 AC: 13

ESP6500EA AF: 0.0206 AC: 172

ExAC AF: 0.0164 AC: 1986

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.025	D
Polyphen		0.86	P
Vest4		0.16
ClinPred		0.016	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.37
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs11766611; hg19: chr7-4830463;