20-17949101-T-C

Position:

• chr20-17949101-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014426.4(SNX5):​c.794A>G​(p.Tyr265Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SNX5 NM_014426.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

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]

SNX5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40214306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX5	NM_014426.4	c.794A>G	p.Tyr265Cys	missense_variant, splice_region_variant	9/13	ENST00000377759.9	NP_055241.1
SNX5	NM_152227.3	c.794A>G	p.Tyr265Cys	missense_variant, splice_region_variant	10/14		NP_689413.1
SNX5	NM_001282454.2	c.479A>G	p.Tyr160Cys	missense_variant, splice_region_variant	9/13		NP_001269383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX5	ENST00000377759.9	c.794A>G	p.Tyr265Cys	missense_variant, splice_region_variant	9/13	1	NM_014426.4	ENSP00000366988.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Nov 29, 2024

The c.794A>G (p.Y265C) alteration is located in exon 10 (coding exon 9) of the SNX5 gene. This alteration results from a A to G substitution at nucleotide position 794, causing the tyrosine (Y) at amino acid position 265 to be replaced by a cysteine (C). 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	0.18
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;D;D;.
REVEL	Benign	0.16
Sift	Benign	0.17	T;T;D;.
Sift4G	Benign	0.070	T;T;T;.
Polyphen		0.024	B;B;.;.
Vest4		0.57
MutPred		0.52		Gain of methylation at K264 (P = 0.0125);Gain of methylation at K264 (P = 0.0125);.;.;
MVP		0.63
MPC		0.42
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr20-17929745;