11-65778402-G-C

Variant names:

• chr11-65778402-G-C
• rs749677161
• NM_138368.5:c.2091C>G
• AP5B1 p.Phe697Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138368.5(AP5B1):​c.2091C>G​(p.Phe697Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,441,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: AP5B1 NM_138368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985
• Publications: 1 publications found

Genes affected

AP5B1 (HGNC:25104): (adaptor related protein complex 5 subunit beta 1) Involved in endosomal transport. Located in lysosomal membrane. Part of AP-type membrane coat adaptor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138368.5. 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
	AP5B1	NM_138368.5	MANE Select	c.2091C>G	p.Phe697Leu	missense	Exon 2 of 2	NP_612377.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP5B1	ENST00000532090.3	TSL:1 MANE Select	c.2091C>G	p.Phe697Leu	missense	Exon 2 of 2	ENSP00000454303.1	Q2VPB7
	AP5B1	ENST00000893259.1		c.1248C>G	p.Phe416Leu	missense	Exon 2 of 2	ENSP00000563318.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000955 AC: 2 AN: 209464 AF XY: 0.00000871

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1441690 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715990

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 41068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 38972

South Asian (SAS) AF: 0.00 AC: 0 AN: 84670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104508

Other (OTH) AF: 0.00 AC: 0 AN: 59824

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.98
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
Sift	Benign	0.26	T
Sift4G	Pathogenic	0.0	D
Varity_R		0.080
gMVP		0.78
Mutation Taster		=80/20	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs749677161;

hg19: chr11-65545873;