14-31084758-GT-GTT

Variant names:

• chr14-31084758-G-GT
• rs766477779
• NM_001128126.3:c.306+4182dupT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The NM_007077.5(AP4S1):​c.367-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,258 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: AP4S1 NM_007077.5 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.422
• Publications: 1 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 -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 2.1541667 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 0 (no position change), new splice context is: attaaggtgtttttttttAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 14-31084758-G-GT is Benign according to our data. Variant chr14-31084758-G-GT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00116 (1695/1461220) while in subpopulation MID AF = 0.0101 (58/5764). AF 95% confidence interval is 0.00799. There are 4 homozygotes in GnomAdExome4. There are 875 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007077.5. 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.306+4182dupT		intron	N/A	NP_001121598.1
	AP4S1	NM_007077.5		c.367-3dupT		splice_acceptor intron	N/A	NP_009008.2
	AP4S1	NM_001254727.2		c.*39-3dupT		splice_acceptor intron	N/A	NP_001241656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4S1	ENST00000542754.7	TSL:1 MANE Select	c.306+4174_306+4175insT		intron	N/A	ENSP00000438170.2
	AP4S1	ENST00000334725.8	TSL:1	c.*39-11_*39-10insT		intron	N/A	ENSP00000334484.4
	AP4S1	ENST00000216366.9	TSL:1	c.*13-11_*13-10insT		intron	N/A	ENSP00000216366.5

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 151922 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00127 AC: 319 AN: 250256 AF XY: 0.00138

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00116 AC: 1695 AN: 1461220 Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 875 AN XY: 726920

African (AFR) AF: 0.000418 AC: 14 AN: 33462

American (AMR) AF: 0.00152 AC: 68 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 84 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00111 AC: 96 AN: 86244

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53364

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5764

European-Non Finnish (NFE) AF: 0.00113 AC: 1256 AN: 1111552

Other (OTH) AF: 0.00169 AC: 102 AN: 60358

GnomAD4 genome AF: 0.00105 AC: 159 AN: 152038 Hom.: 3 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74330

African (AFR) AF: 0.000241 AC: 10 AN: 41456

American (AMR) AF: 0.00197 AC: 30 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4806

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 67974

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00118

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs766477779; hg19: chr14-31553964; COSMIC: COSV99364439; COSMIC: COSV99364439;