rs114734921

Variant names:

• chr1-113895826-T-C
• rs114734921
• NM_001253852.3:c.1723A>G
• AP4B1 p.Ile575Val

Your query was ambiguous. Multiple possible variants found:

• chr1-113895826-T-C
• chr1-113895826-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001253852.3(AP4B1):​c.1723A>G​(p.Ile575Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,614,224 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I575S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (40 hom.)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.849
• Publications: 10 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=0.004743427).
• BP6: Variant 1-113895826-T-C is Benign according to our data. Variant chr1-113895826-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00395 (601/152338) while in subpopulation NFE AF = 0.00612 (416/68024). AF 95% confidence interval is 0.00563. There are 10 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.1723A>G	p.Ile575Val	missense	Exon 9 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.1723A>G	p.Ile575Val	missense	Exon 10 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.1723A>G	p.Ile575Val	missense	Exon 10 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.1723A>G	p.Ile575Val	missense	Exon 9 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.1723A>G	p.Ile575Val	missense	Exon 10 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.1849A>G	p.Ile617Val	missense	Exon 10 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 602 AN: 152220 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00373 AC: 939 AN: 251438 AF XY: 0.00394

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00580 AC: 8476 AN: 1461886 Hom.: 40 Cov.: 31 AF XY: 0.00566 AC XY: 4113 AN XY: 727242

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00242 AC: 108 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86258

European-Finnish (FIN) AF: 0.00294 AC: 157 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.00695 AC: 7724 AN: 1112008

Other (OTH) AF: 0.00482 AC: 291 AN: 60396

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152338 Hom.: 10 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74494

African (AFR) AF: 0.000866 AC: 36 AN: 41574

American (AMR) AF: 0.00333 AC: 51 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00612 AC: 416 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00519 Hom.: 11

Bravo AF: 0.00426

EpiCase AF: 0.00627

EpiControl AF: 0.00759

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary spastic paraplegia 47 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.85
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.069
Sift	Benign	0.40	T
Sift4G	Benign	0.42	T
Varity_R		0.054
gMVP		0.14
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs114734921;

hg19: chr1-114438448;