chr3-94014527-T-C

Variant names:

• chr3-94014527-T-C
• NM_001001850.3:c.743A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001001850.3(STX19):​c.743A>G​(p.Asn248Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STX19 NM_001001850.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STX19	NM_001001850.3	c.743A>G	p.Asn248Ser	missense_variant	Exon 2 of 2	ENST00000315099.3	NP_001001850.1
ARL13B	NM_001174150.2	c.380+10619T>C		intron_variant	Intron 3 of 9	ENST00000394222.8	NP_001167621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STX19	ENST00000315099.3	c.743A>G	p.Asn248Ser	missense_variant	Exon 2 of 2	1	NM_001001850.3	ENSP00000320679.2
ARL13B	ENST00000394222.8	c.380+10619T>C		intron_variant	Intron 3 of 9	1	NM_001174150.2	ENSP00000377769.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743A>G (p.N248S) alteration is located in exon 2 (coding exon 1) of the STX19 gene. This alteration results from a A to G substitution at nucleotide position 743, causing the asparagine (N) at amino acid position 248 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Uncertain	0.014	D
Sift4G	Benign	0.067	T
Polyphen		0.062	B
Vest4		0.55
MutPred		0.64		Gain of disorder (P = 0.0833);
MVP		0.72
MPC		0.018
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.20

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-93733371;