11-65778400-C-A

Variant names:

• chr11-65778400-C-A
• rs745327454
• NM_138368.5:c.2093G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138368.5(AP5B1):​c.2093G>T​(p.Arg698Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,442,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R698H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP5B1 NM_138368.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18293056).

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.2093G>T	p.Arg698Leu	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.2093G>T	p.Arg698Leu	missense	Exon 2 of 2	ENSP00000454303.1	Q2VPB7
	AP5B1	ENST00000893259.1		c.1250G>T	p.Arg417Leu	missense	Exon 2 of 2	ENSP00000563318.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000475 AC: 1 AN: 210632 AF XY: 0.00000865

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: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1442388 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2 AN XY: 716416

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

American (AMR) AF: 0.00 AC: 0 AN: 41174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 38992

South Asian (SAS) AF: 0.00 AC: 0 AN: 84760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104730

Other (OTH) AF: 0.0000167 AC: 1 AN: 59858

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000832 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.18	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.066
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
Vest4		0.17
MVP		0.45
MPC		0.079
GERP RS		1.6
Varity_R		0.15
gMVP		0.54
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs745327454; hg19: chr11-65545871;