5-115913381-C-T

Variant names:

• chr5-115913381-C-T
• rs7733604
• NM_001284.4:c.473C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001284.4(AP3S1):​c.473C>T​(p.Pro158Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (0 hom., cov: 39)
  • Exomes 𝑓: 0.48 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: AP3S1 NM_001284.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.81
• Publications: 18 publications found

Genes affected

AP3S1 (HGNC:2013): (adaptor related protein complex 3 subunit sigma 1) This gene encodes a subunit of the AP3 adaptor complex. This complex functions in the formation of subcellular vesicles budded from the Golgi body. Several related pseudogenes of this gene have been found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027187169).
• BP6: Variant 5-115913381-C-T is Benign according to our data. Variant chr5-115913381-C-T is described in ClinVar as Benign. ClinVar VariationId is 769304.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001284.4. 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
	AP3S1	NM_001284.4	MANE Select	c.473C>T	p.Pro158Leu	missense	Exon 6 of 6	NP_001275.1	Q92572
	AP3S1	NM_001364119.1		c.521C>T	p.Pro174Leu	missense	Exon 7 of 7	NP_001351048.1
	AP3S1	NM_001002924.3		c.407C>T	p.Pro136Leu	missense	Exon 7 of 7	NP_001002924.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP3S1	ENST00000316788.12	TSL:1 MANE Select	c.473C>T	p.Pro158Leu	missense	Exon 6 of 6	ENSP00000325369.7	Q92572
	AP3S1	ENST00000395548.6	TSL:1	n.550C>T		non_coding_transcript_exon	Exon 7 of 7
	AP3S1	ENST00000922028.1		c.623C>T	p.Pro208Leu	missense	Exon 6 of 6	ENSP00000592087.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 29834 AN: 76788 Hom.: 0 Cov.: 39

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.397

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.489 AC: 90608 AN: 185178 AF XY: 0.490

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.497

Gnomad EAS exome AF: 0.463

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.494

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.479 AC: 457274 AN: 954664 Hom.: 10 Cov.: 59 AF XY: 0.481 AC XY: 233976 AN XY: 486882

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.488 AC: 11464 AN: 23514

American (AMR) AF: 0.491 AC: 19178 AN: 39082

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 10215 AN: 20840

East Asian (EAS) AF: 0.453 AC: 12623 AN: 27868

South Asian (SAS) AF: 0.491 AC: 35250 AN: 71720

European-Finnish (FIN) AF: 0.494 AC: 21362 AN: 43264

Middle Eastern (MID) AF: 0.317 AC: 1476 AN: 4658

European-Non Finnish (NFE) AF: 0.478 AC: 325684 AN: 682030

Other (OTH) AF: 0.480 AC: 20022 AN: 41688

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.389 AC: 29880 AN: 76888 Hom.: 0 Cov.: 39 AF XY: 0.384 AC XY: 14580 AN XY: 37976

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.391 AC: 8155 AN: 20850

American (AMR) AF: 0.377 AC: 2918 AN: 7730

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 681 AN: 1740

East Asian (EAS) AF: 0.311 AC: 795 AN: 2560

South Asian (SAS) AF: 0.390 AC: 967 AN: 2480

European-Finnish (FIN) AF: 0.382 AC: 2125 AN: 5558

Middle Eastern (MID) AF: 0.388 AC: 45 AN: 116

European-Non Finnish (NFE) AF: 0.396 AC: 13607 AN: 34318

Other (OTH) AF: 0.399 AC: 433 AN: 1086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.463 Hom.: 5

ExAC AF: 0.469 AC: 56993

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.28
Sift	Benign	0.052	T
Sift4G	Benign	0.20	T
Polyphen		0.047	B
Vest4		0.22
MPC		0.72
ClinPred		0.036	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.75
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs7733604; hg19: chr5-115249078; COSMIC: COSV57473169;