Genetic Variant AP4B1:p.Thr719Lys (chr1-113895129-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001253852.3(AP4B1):c.2156C>A(p.Thr719Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. T719M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AP4B1
NM_001253852.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.688

Publications

2 publications found

Variant links:

Genes affected

AP4B1 (HGNC:572): (adaptor related protein complex 4 subunit beta 1) This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AP4B1 links:

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

AP4B1-AS1 links:

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ACMG classification

Classification was made for transcript

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=0.090399).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001253852.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP4B1	NM_001253852.3	MANE Select	c.2156C>A	p.Thr719Lys	missense	Exon 10 of 10	NP_001240781.1	Q9Y6B7-1
AP4B1	NM_001438373.1		c.2156C>A	p.Thr719Lys	missense	Exon 11 of 11	NP_001425302.1
AP4B1	NM_006594.5		c.2156C>A	p.Thr719Lys	missense	Exon 11 of 11	NP_006585.2	Q9Y6B7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP4B1	ENST00000369569.6	TSL:1 MANE Select	c.2156C>A	p.Thr719Lys	missense	Exon 10 of 10	ENSP00000358582.1	Q9Y6B7-1
AP4B1	ENST00000256658.8	TSL:1	c.2156C>A	p.Thr719Lys	missense	Exon 11 of 11	ENSP00000256658.4	Q9Y6B7-1
AP4B1	ENST00000863127.1		c.2282C>A	p.Thr761Lys	missense	Exon 11 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251246

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.089

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.82

M_CAP

Benign

0.019

MetaRNN

Benign

0.090

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

0.69

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.70

REVEL

Benign

0.032

Sift

Benign

0.20

Sift4G

Uncertain

0.041

Polyphen

0.48

Vest4

0.082

MutPred

0.59

Gain of solvent accessibility (P = 0.012)

MVP

0.61

MPC

0.15

ClinPred

0.082

GERP RS

2.6

Varity_R

0.026

gMVP

0.67

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over