rs147135554

Variant names:

• chr14-31066225-A-G
• rs147135554
• NM_001128126.3:c.29A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001128126.3(AP4S1):​c.29A>G​(p.Lys10Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,614,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (2 hom.)
• Consequence: AP4S1 NM_001128126.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.09
• Publications: 5 publications found

Genes affected

AP4S1 (HGNC:575): (adaptor related protein complex 4 subunit sigma 1) This gene encodes a member of the adaptor complexes small subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

AP4S1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 52

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015460998).
• BP6: Variant 14-31066225-A-G is Benign according to our data. Variant chr14-31066225-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434248.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128126.3. 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
	AP4S1	NM_001128126.3	MANE Select	c.29A>G	p.Lys10Arg	missense	Exon 2 of 6	NP_001121598.1	Q9Y587-1
	AP4S1	NM_007077.5		c.29A>G	p.Lys10Arg	missense	Exon 2 of 6	NP_009008.2
	AP4S1	NM_001254727.2		c.29A>G	p.Lys10Arg	missense	Exon 2 of 7	NP_001241656.1	Q9Y587-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.29A>G	p.Lys10Arg	missense	Exon 2 of 6	ENSP00000438170.2	Q9Y587-1
	AP4S1	ENST00000334725.8	TSL:1	c.29A>G	p.Lys10Arg	missense	Exon 2 of 7	ENSP00000334484.4	Q9Y587-4
	AP4S1	ENST00000216366.9	TSL:1	c.29A>G	p.Lys10Arg	missense	Exon 1 of 5	ENSP00000216366.5	A0A8C8KBR5

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000621 AC: 156 AN: 251350 AF XY: 0.000559

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000811 AC: 1185 AN: 1461734 Hom.: 2 Cov.: 31 AF XY: 0.000771 AC XY: 561 AN XY: 727166

African (AFR) AF: 0.000807 AC: 27 AN: 33468

American (AMR) AF: 0.00170 AC: 76 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000934 AC: 1038 AN: 1111936

Other (OTH) AF: 0.000696 AC: 42 AN: 60386

GnomAD4 genome AF: 0.000886 AC: 135 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74482

African (AFR) AF: 0.000481 AC: 20 AN: 41580

American (AMR) AF: 0.00399 AC: 61 AN: 15294

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000738 Hom.: 0

Bravo AF: 0.000979

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 52 (1)
-	1	-	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.065	N
PhyloP100		4.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.046	B
Vest4		0.28
MVP		0.28
MPC		0.13
ClinPred		0.030	T
GERP RS		4.8
PromoterAI		-0.029	Neutral
Varity_R		0.20
gMVP		0.24
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs147135554; hg19: chr14-31535431;