rs141417436

Variant names:

• chr1-113900263-A-G
• rs141417436
• NM_001253852.3:c.755T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001253852.3(AP4B1):​c.755T>C​(p.Val252Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00191 in 1,606,648 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 6.06
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010090083).
• BP6: Variant 1-113900263-A-G is Benign according to our data. Variant chr1-113900263-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 386852.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00155 (236/152308) while in subpopulation NFE AF = 0.00253 (172/68030). AF 95% confidence interval is 0.00222. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.755T>C	p.Val252Ala	missense	Exon 5 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.755T>C	p.Val252Ala	missense	Exon 6 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.755T>C	p.Val252Ala	missense	Exon 6 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.755T>C	p.Val252Ala	missense	Exon 5 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.755T>C	p.Val252Ala	missense	Exon 6 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.755T>C	p.Val252Ala	missense	Exon 5 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00116 AC: 288 AN: 247764 AF XY: 0.00131

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00195 AC: 2829 AN: 1454340 Hom.: 2 Cov.: 30 AF XY: 0.00188 AC XY: 1359 AN XY: 722540

African (AFR) AF: 0.000121 AC: 4 AN: 33100

American (AMR) AF: 0.000228 AC: 10 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.000327 AC: 28 AN: 85616

European-Finnish (FIN) AF: 0.000563 AC: 30 AN: 53266

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5730

European-Non Finnish (NFE) AF: 0.00243 AC: 2689 AN: 1107316

Other (OTH) AF: 0.00107 AC: 64 AN: 60012

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74480

African (AFR) AF: 0.000337 AC: 14 AN: 41562

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68030

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00214 Hom.: 0

Bravo AF: 0.00161

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.00245

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spastic paraplegia 47 (2)
-	1	1	not provided (2)
-	1	1	not specified (2)
-	-	1	AP4B1-related disorder (1)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.18
Sift	Benign	0.078	T
Sift4G	Benign	0.20	T
Polyphen		0.97	D
Vest4		0.71
MVP		0.60
MPC		0.21
ClinPred		0.067	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.49
Mutation Taster		=84/16	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

Other links and lift over

dbSNP: rs141417436; hg19: chr1-114442885;