1-113901822-T-G

Variant names:

• chr1-113901822-T-G
• rs34751342
• NM_001253852.3:c.402A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001253852.3(AP4B1):​c.402A>C​(p.Ser134Ser) 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:7
• Conservation: PhyloP100: -0.468
• Publications: 11 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 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 47

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.402A>C	p.Ser134Ser	synonymous	Exon 3 of 10	NP_001240781.1	Q9Y6B7-1
	AP4B1	NM_001438373.1		c.402A>C	p.Ser134Ser	synonymous	Exon 4 of 11	NP_001425302.1
	AP4B1	NM_006594.5		c.402A>C	p.Ser134Ser	synonymous	Exon 4 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.402A>C	p.Ser134Ser	synonymous	Exon 3 of 10	ENSP00000358582.1	Q9Y6B7-1
	AP4B1	ENST00000256658.8	TSL:1	c.402A>C	p.Ser134Ser	synonymous	Exon 4 of 11	ENSP00000256658.4	Q9Y6B7-1
	AP4B1	ENST00000863127.1		c.402A>C	p.Ser134Ser	synonymous	Exon 3 of 11	ENSP00000533186.1

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

GnomAD2 exomes AF: 0.0364 AC: 9151 AN: 251470 AF XY: 0.0394

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 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

African (AFR) AF: 0.00615 AC: 206 AN: 33480

American (AMR) AF: 0.0169 AC: 757 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 2048 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39690

South Asian (SAS) AF: 0.0673 AC: 5806 AN: 86258

European-Finnish (FIN) AF: 0.0281 AC: 1501 AN: 53416

Middle Eastern (MID) AF: 0.0435 AC: 251 AN: 5768

European-Non Finnish (NFE) AF: 0.0414 AC: 46069 AN: 1111998

Other (OTH) AF: 0.0408 AC: 2467 AN: 60394

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

African (AFR) AF: 0.00696 AC: 289 AN: 41548

American (AMR) AF: 0.0250 AC: 382 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 280 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0562 AC: 271 AN: 4822

European-Finnish (FIN) AF: 0.0226 AC: 240 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0414 AC: 2818 AN: 68014

Other (OTH) AF: 0.0293 AC: 62 AN: 2116

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 47 (2)
-	-	2	not specified (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	-0.85
CADD	Benign	1.2
DANN	Benign	0.67
PhyloP100		-0.47
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: rs34751342; hg19: chr1-114444444; COSMIC: COSV56724926; COSMIC: COSV56724926;