7-4788226-C-G

Variant names:

• chr7-4788226-C-G
• NM_014855.3:c.1527C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014855.3(AP5Z1):​c.1527C>G​(p.Phe509Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F509F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11836895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1527C>G	p.Phe509Leu	missense_variant	Exon 12 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.1059C>G	p.Phe353Leu	missense_variant	Exon 11 of 16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1191C>G	p.Phe397Leu	missense_variant	Exon 10 of 15		XP_047277054.1
AP5Z1	NR_157345.1	n.1658C>G		non_coding_transcript_exon_variant	Exon 12 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1527C>G	p.Phe509Leu	missense_variant	Exon 12 of 17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1421186 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.067
Sift	Benign	0.48	T;.
Sift4G	Benign	0.73	T;.
Polyphen		0.012	B;B
Vest4		0.14
MutPred		0.37		Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);
MVP		0.030
ClinPred		0.070	T
GERP RS		0.34
Varity_R		0.080
gMVP		0.37

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-4827857;