3-94014416-C-T

Variant names:

• chr3-94014416-C-T
• rs1373470767
• NM_001001850.3:c.854G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001001850.3(STX19):​c.854G>A​(p.Cys285Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000213 in 1,410,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STX19 NM_001001850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• Publications: 0 publications found

Genes affected

STX19 (HGNC:19300): (syntaxin 19) Predicted to enable SNAP receptor activity and SNARE binding activity. Predicted to be involved in intracellular protein transport; synaptic vesicle fusion to presynaptic active zone membrane; and vesicle docking. Predicted to be part of SNARE complex. Predicted to be active in presynaptic active zone membrane and synaptic vesicle. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARL13B (HGNC:25419): (ADP ribosylation factor like GTPase 13B) This gene encodes a member of the ADP-ribosylation factor-like family. The encoded protein is a small GTPase that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. This protein is localized in the cilia and plays a role in cilia formation and in maintenance of cilia. Mutations in this gene are the cause of Joubert syndrome 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ARL13B Gene-Disease associations (from GenCC):

• Joubert syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Joubert syndrome 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001850.3. 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
	STX19	NM_001001850.3	MANE Select	c.854G>A	p.Cys285Tyr	missense	Exon 2 of 2	NP_001001850.1	Q8N4C7
	ARL13B	NM_001174150.2	MANE Select	c.380+10508C>T		intron	N/A	NP_001167621.1	Q3SXY8-1
	ARL13B	NM_182896.3		c.380+10508C>T		intron	N/A	NP_878899.1	Q3SXY8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX19	ENST00000315099.3	TSL:1 MANE Select	c.854G>A	p.Cys285Tyr	missense	Exon 2 of 2	ENSP00000320679.2	Q8N4C7
	ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.380+10508C>T		intron	N/A	ENSP00000377769.3	Q3SXY8-1
	ARL13B	ENST00000471138.5	TSL:1	c.380+10508C>T		intron	N/A	ENSP00000420780.1	Q3SXY8-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000978 AC: 2 AN: 204464 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000122

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1410318 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699064

African (AFR) AF: 0.00 AC: 0 AN: 31100

American (AMR) AF: 0.00 AC: 0 AN: 32844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22436

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39402

South Asian (SAS) AF: 0.00 AC: 0 AN: 74806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094574

Other (OTH) AF: 0.00 AC: 0 AN: 58214

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.64		Gain of sheet (P = 0.0011)
MVP		0.82
MPC		0.0089
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.50
Mutation Taster		=54/46	polymorphism

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: rs1373470767; hg19: chr3-93733260;