NM_001253852.3:c.1365T>C

Variant names:

• chr1-113896403-A-G
• rs114201291
• NM_001253852.3:c.1365T>C

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.1365T>C​(p.Tyr455Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,204 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 33)
  • Exomes 𝑓: 0.019 (324 hom.)
• Consequence: AP4B1 NM_001253852.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.18
• Publications: 4 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 (BayesDel_noAF=-0.55).
• BP6: Variant 1-113896403-A-G is Benign according to our data. Variant chr1-113896403-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157717.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 = 0.0143 (2183/152314) while in subpopulation NFE AF = 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 24 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.1365T>C	p.Tyr455Tyr	synonymous	Exon 8 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.1365T>C	p.Tyr455Tyr	synonymous	Exon 9 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.1365T>C	p.Tyr455Tyr	synonymous	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.1365T>C	p.Tyr455Tyr	synonymous	Exon 8 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.1365T>C	p.Tyr455Tyr	synonymous	Exon 9 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.1491T>C	p.Tyr497Tyr	synonymous	Exon 9 of 11	ENSP00000533186.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2183 AN: 152196 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0152 AC: 3816 AN: 251280 AF XY: 0.0158

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0195 AC: 28474 AN: 1461890 Hom.: 324 Cov.: 32 AF XY: 0.0195 AC XY: 14169 AN XY: 727244

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.0111 AC: 498 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 283 AN: 26136

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

South Asian (SAS) AF: 0.00722 AC: 623 AN: 86258

European-Finnish (FIN) AF: 0.0123 AC: 658 AN: 53420

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.0227 AC: 25288 AN: 1112010

Other (OTH) AF: 0.0159 AC: 961 AN: 60394

GnomAD4 genome AF: 0.0143 AC: 2183 AN: 152314 Hom.: 24 Cov.: 33 AF XY: 0.0136 AC XY: 1012 AN XY: 74482

African (AFR) AF: 0.00399 AC: 166 AN: 41580

American (AMR) AF: 0.0148 AC: 227 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4830

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1560 AN: 68024

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0193 Hom.: 20

Bravo AF: 0.0149

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0236

EpiControl AF: 0.0236

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary spastic paraplegia 47 (2)
-	-	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
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.73
PhyloP100		1.2
Mutation Taster		=100/0	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: rs114201291; hg19: chr1-114439025;