20-17968383-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014426.4(SNX5):c.43C>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000267 in 1,125,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SNX5 NM_014426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

SNX5 (HGNC:14969): (sorting nexin 5) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein functions in endosomal sorting, the phosphoinositide-signaling pathway, and macropinocytosis. This gene may play a role in the tumorigenesis of papillary thyroid carcinoma. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

OVOL2 (HGNC:15804): (ovo like zinc finger 2) This gene encodes a member of the evolutionarily conserved ovo-like protein family. Mammalian members of this family contain a single zinc finger domain composed of a tetrad of C2H2 zinc fingers with variable N- and C-terminal extensions that contain intrinsically disordered domains. Members of this family are involved in epithelial development and differentiation. Knockout of this gene in mouse results in early embryonic lethality with phenotypes that include neurectoderm expansion, impaired vascularization, and heart anomalies. In humans, allelic variants of this gene have been associated with posterior polymorphous corneal dystrophy. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10213068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX5	NM_014426.4	c.43C>G	p.Arg15Gly	missense_variant	1/13	ENST00000377759.9
SNX5	NM_152227.3	c.43C>G	p.Arg15Gly	missense_variant	2/14
SNX5	NM_001282454.2	c.-265+317C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX5	ENST00000377759.9	c.43C>G	p.Arg15Gly	missense_variant	1/13	1	NM_014426.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000267 AC: 3 AN: 1125038 Hom.: 0 Cov.: 31 AF XY: 0.00000374 AC XY: 2 AN XY: 534726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000374

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000443

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.43C>G (p.R15G) alteration is located in exon 2 (coding exon 1) of the SNX5 gene. This alteration results from a C to G substitution at nucleotide position 43, causing the arginine (R) at amino acid position 15 to be replaced by a glycine (G). 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	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;T;T;.;T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.23	N
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.;.;N;.;.;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N;N;N;D;.;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.16	T;T;T;D;.;.;.;.
Sift4G	Benign	0.36	T;T;T;.;.;.;.;.
Polyphen		0.0030	B;B;.;.;.;.;.;.
Vest4		0.22
MutPred		0.27		Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);
MVP		0.21
MPC		0.092
ClinPred		0.17	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.33

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: chr20-17949026;