1-113901822-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001253852.3(AP4B1):c.402A>C(p.Ser134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,614,146 control chromosomes in the GnomAD database, including 1,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S134S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (112 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1466 hom.)
• Consequence: AP4B1 NM_001253852.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.468

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-113901822-T-G is Benign according to our data. Variant chr1-113901822-T-G is described in ClinVar as [Benign]. Clinvar id is 157722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.468 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4B1	NM_001253852.3	c.402A>C	p.Ser134=	synonymous_variant	3/10	ENST00000369569.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6	c.402A>C	p.Ser134=	synonymous_variant	3/10	1	NM_001253852.3	P1

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4383 AN: 152168 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.00698

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0806

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0364 AC: 9151 AN: 251470 Hom.: 257 AF XY: 0.0394 AC XY: 5350 AN XY: 135906

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0797

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0676

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0404 AC: 59114 AN: 1461860 Hom.: 1466 Cov.: 32 AF XY: 0.0417 AC XY: 30304 AN XY: 727226

Gnomad4 AFR exome AF: 0.00615

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0784

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.0414

Gnomad4 OTH exome AF: 0.0408

GnomAD4 genome AF: 0.0288 AC: 4387 AN: 152286 Hom.: 112 Cov.: 32 AF XY: 0.0286 AC XY: 2132 AN XY: 74466

Gnomad4 AFR AF: 0.00696

Gnomad4 AMR AF: 0.0250

Gnomad4 ASJ AF: 0.0806

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0562

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.0414

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0360 Hom.: 62

Bravo AF: 0.0273

Asia WGS AF: 0.0260 AC: 89 AN: 3478

EpiCase AF: 0.0397

EpiControl AF: 0.0382

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 47 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2016

This alteration is classified as 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. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.2
Dann	Benign	0.67

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: rs34751342; hg19: chr1-114444444; COSMIC: COSV56724926; COSMIC: COSV56724926;