rs11549840

Variant names:

• chr7-4781721-G-C
• rs11549840
• NM_014855.3:c.333G>C

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.333G>C​(p.Gln111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,581,108 control chromosomes in the GnomAD database, including 442 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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 (409 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0780
• Publications: 8 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=0.003640473).
• BP6: Variant 7-4781721-G-C is Benign according to our data. Variant chr7-4781721-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128414.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 (2438/152358) while in subpopulation SAS AF = 0.0252 (122/4834). AF 95% confidence interval is 0.0226. There are 33 homozygotes in GnomAd4. There are 1153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.333G>C	p.Gln111His	missense	Exon 3 of 17	NP_055670.1	O43299-1
	AP5Z1	NM_001364858.1		c.-103+409G>C		intron	N/A	NP_001351787.1
	AP5Z1	NR_157345.1		n.426G>C		non_coding_transcript_exon	Exon 3 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5Z1	ENST00000649063.2	MANE Select	c.333G>C	p.Gln111His	missense	Exon 3 of 17	ENSP00000497815.1	O43299-1
	AP5Z1	ENST00000865634.1		c.333G>C	p.Gln111His	missense	Exon 3 of 18	ENSP00000535693.1
	AP5Z1	ENST00000865636.1		c.333G>C	p.Gln111His	missense	Exon 3 of 17	ENSP00000535695.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2438 AN: 152240 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0172 AC: 4117 AN: 238736 AF XY: 0.0179

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00625

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0213 AC: 30392 AN: 1428750 Hom.: 409 Cov.: 31 AF XY: 0.0216 AC XY: 15201 AN XY: 703550

African (AFR) AF: 0.00376 AC: 124 AN: 32942

American (AMR) AF: 0.0149 AC: 654 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 826 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38770

South Asian (SAS) AF: 0.0228 AC: 1936 AN: 84990

European-Finnish (FIN) AF: 0.00676 AC: 349 AN: 51658

Middle Eastern (MID) AF: 0.0489 AC: 277 AN: 5664

European-Non Finnish (NFE) AF: 0.0228 AC: 24827 AN: 1086556

Other (OTH) AF: 0.0238 AC: 1399 AN: 58820

GnomAD4 genome AF: 0.0160 AC: 2438 AN: 152358 Hom.: 33 Cov.: 33 AF XY: 0.0155 AC XY: 1153 AN XY: 74504

African (AFR) AF: 0.00428 AC: 178 AN: 41588

American (AMR) AF: 0.0179 AC: 274 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0252 AC: 122 AN: 4834

European-Finnish (FIN) AF: 0.00631 AC: 67 AN: 10622

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1601 AN: 68034

Other (OTH) AF: 0.0236 AC: 50 AN: 2116

Alfa AF: 0.0220 Hom.: 7

Bravo AF: 0.0172

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.00305 AC: 13

ESP6500EA AF: 0.0241 AC: 205

ExAC AF: 0.0170 AC: 2058

Asia WGS AF: 0.00895 AC: 31 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	0.22
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.078
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.039
Sift	Benign	0.67	T
Sift4G	Uncertain	0.015	D
Polyphen		0.083	B
Vest4		0.14
MutPred		0.29		Loss of helix (P = 0.079)
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.039
gMVP		0.30
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11549840; hg19: chr7-4821352;