Genetic Variant NM_001253852.3:c.955T>C (chr1-113900063-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_001253852.3(AP4B1):c.955T>C(p.Phe319Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AP4B1
NM_001253852.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.04

Publications

3 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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

PP5

Variant 1-113900063-A-G is Pathogenic according to our data. Variant chr1-113900063-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402201.Status of the report is criteria_provided_single_submitter, 1 stars.

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
AP4B1	NM_001253852.3	MANE Select	c.955T>C	p.Phe319Leu	missense	Exon 5 of 10	NP_001240781.1
AP4B1	NM_001438373.1		c.955T>C	p.Phe319Leu	missense	Exon 6 of 11	NP_001425302.1
AP4B1	NM_006594.5		c.955T>C	p.Phe319Leu	missense	Exon 6 of 11	NP_006585.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP4B1	ENST00000369569.6	TSL:1 MANE Select	c.955T>C	p.Phe319Leu	missense	Exon 5 of 10	ENSP00000358582.1
AP4B1	ENST00000256658.8	TSL:1	c.955T>C	p.Phe319Leu	missense	Exon 6 of 11	ENSP00000256658.4
AP4B1	ENST00000863127.1		c.955T>C	p.Phe319Leu	missense	Exon 5 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Abnormal brain morphology (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

3.1

PhyloP100

9.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.56

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.96

MutPred

0.57

Loss of methylation at K317 (P = 0.0926)

MVP

0.53

MPC

0.62

ClinPred

0.99

GERP RS

5.0

Varity_R

0.75

gMVP

0.74

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over