7-4787750-G-C

Variant names:

• chr7-4787750-G-C
• NM_014855.3:c.1428G>C

Variant summary

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

The NM_014855.3(AP5Z1):​c.1428G>C​(p.Leu476Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,772 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP5Z1 NM_014855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP5Z1	NM_014855.3	c.1428G>C	p.Leu476Phe	missense_variant	Exon 11 of 17	ENST00000649063.2	NP_055670.1
AP5Z1	NM_001364858.1	c.960G>C	p.Leu320Phe	missense_variant	Exon 10 of 16		NP_001351787.1
AP5Z1	XM_047421098.1	c.1092G>C	p.Leu364Phe	missense_variant	Exon 9 of 15		XP_047277054.1
AP5Z1	NR_157345.1	n.1559G>C		non_coding_transcript_exon_variant	Exon 11 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP5Z1	ENST00000649063.2	c.1428G>C	p.Leu476Phe	missense_variant	Exon 11 of 17		NM_014855.3	ENSP00000497815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390772 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686572

Gnomad4 AFR exome AF: 0.0000315

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: 9.26e-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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.48		Loss of catalytic residue at L476 (P = 0.0626);Loss of catalytic residue at L476 (P = 0.0626);
MVP		0.18
ClinPred		0.97	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.64

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: chr7-4827381;