rs1217401

Variant names:

• chr1-113896329-A-G
• rs1217401
• NM_001253852.3:c.1439T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001253852.3(AP4B1):​c.1439T>C​(p.Leu480Ser) variant causes a missense change. The variant allele was found at a frequency of 0.324 in 1,613,954 control chromosomes in the GnomAD database, including 93,103 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15526 hom., cov: 32)
  • Exomes 𝑓: 0.32 (77577 hom.)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.28
• Publications: 51 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.6311914E-6).
• BP6: Variant 1-113896329-A-G is Benign according to our data. Variant chr1-113896329-A-G is described in ClinVar as Benign. ClinVar VariationId is 157718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	NM_001253852.3	MANE Select	c.1439T>C	p.Leu480Ser	missense	Exon 8 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.1439T>C	p.Leu480Ser	missense	Exon 9 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.1439T>C	p.Leu480Ser	missense	Exon 9 of 11	NP_006585.2	Q9Y6B7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4B1	ENST00000369569.6	TSL:1 MANE Select	c.1439T>C	p.Leu480Ser	missense	Exon 8 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.1439T>C	p.Leu480Ser	missense	Exon 9 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.1565T>C	p.Leu522Ser	missense	Exon 9 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61944 AN: 152038 Hom.: 15498 Cov.: 32

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.0768

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.380

GnomAD2 exomes AF: 0.303 AC: 76210 AN: 251314 AF XY: 0.304

Gnomad AFR exome AF: 0.720

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.315 AC: 461123 AN: 1461798 Hom.: 77577 Cov.: 47 AF XY: 0.315 AC XY: 229057 AN XY: 727202

African (AFR) AF: 0.724 AC: 24235 AN: 33480

American (AMR) AF: 0.181 AC: 8102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 10659 AN: 26136

East Asian (EAS) AF: 0.0949 AC: 3764 AN: 39664

South Asian (SAS) AF: 0.323 AC: 27825 AN: 86256

European-Finnish (FIN) AF: 0.273 AC: 14580 AN: 53418

Middle Eastern (MID) AF: 0.358 AC: 2066 AN: 5768

European-Non Finnish (NFE) AF: 0.315 AC: 349933 AN: 1111960

Other (OTH) AF: 0.330 AC: 19959 AN: 60392

GnomAD4 genome AF: 0.408 AC: 62021 AN: 152156 Hom.: 15526 Cov.: 32 AF XY: 0.399 AC XY: 29696 AN XY: 74376

African (AFR) AF: 0.705 AC: 29254 AN: 41492

American (AMR) AF: 0.257 AC: 3930 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1385 AN: 3468

East Asian (EAS) AF: 0.0770 AC: 399 AN: 5184

South Asian (SAS) AF: 0.301 AC: 1452 AN: 4826

European-Finnish (FIN) AF: 0.257 AC: 2724 AN: 10584

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21672 AN: 68002

Other (OTH) AF: 0.377 AC: 795 AN: 2108

Alfa AF: 0.342 Hom.: 50239

Bravo AF: 0.415

TwinsUK AF: 0.335 AC: 1244

ALSPAC AF: 0.321 AC: 1238

ESP6500AA AF: 0.685 AC: 3017

ESP6500EA AF: 0.312 AC: 2679

ExAC AF: 0.319 AC: 38671

Asia WGS AF: 0.216 AC: 753 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.312

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spastic paraplegia 47 (3)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0000066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		6.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.082
Sift	Benign	0.38	T
Sift4G	Benign	0.080	T
Polyphen		0.0080	B
Vest4		0.17
MPC		0.21
ClinPred		0.022	T
GERP RS		6.0
Varity_R		0.083
gMVP		0.34
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1217401; hg19: chr1-114438951;