1-113895186-T-A

Variant names:

• chr1-113895186-T-A
• NM_001253852.3:c.2099A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001253852.3(AP4B1):​c.2099A>T​(p.Glu700Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121956974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4B1	NM_001253852.3	c.2099A>T	p.Glu700Val	missense_variant	Exon 10 of 10	ENST00000369569.6	NP_001240781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4B1	ENST00000369569.6	c.2099A>T	p.Glu700Val	missense_variant	Exon 10 of 10	1	NM_001253852.3	ENSP00000358582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 47 Uncertain:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 700 of the AP4B1 protein (p.Glu700Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AP4B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1411592). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.089
Sift	Benign	0.030	D;T;T
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.17	B;B;B
Vest4		0.23
MutPred		0.50		.;Loss of disorder (P = 0.0174);Loss of disorder (P = 0.0174);
MVP		0.62
MPC		0.18
ClinPred		0.16	T
GERP RS		1.9
Varity_R		0.074
gMVP		0.55

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: chr1-114437808; COSMIC: COSV56726733; COSMIC: COSV56726733;