rs1160123121

Variant names:

• chr1-113895109-C-G
• rs1160123121
• NM_001253852.3:c.2176G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001253852.3(AP4B1):​c.2176G>C​(p.Val726Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.44

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16585341).
• BP6: Variant 1-113895109-C-G is Benign according to our data. Variant chr1-113895109-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3404481.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4B1	NM_001253852.3	c.2176G>C	p.Val726Leu	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.2176G>C	p.Val726Leu	missense_variant	Exon 10 of 10	1	NM_001253852.3	ENSP00000358582.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Oct 23, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.041
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.055	T;T;T
Sift4G	Uncertain	0.055	T;T;T
Polyphen		0.30	B;B;B
Vest4		0.20
MutPred		0.49		.;Gain of catalytic residue at V726 (P = 0.1255);Gain of catalytic residue at V726 (P = 0.1255);
MVP		0.68
MPC		0.12
ClinPred		0.27	T
GERP RS		3.8
Varity_R		0.045
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1160123121; hg19: chr1-114437731;