3-125469485-C-T

Variant names:

• chr3-125469485-C-T
• NM_003794.4:c.823G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003794.4(SNX4):​c.823G>A​(p.Gly275Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNX4 NM_003794.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

Genes affected

SNX4 (HGNC:11175): (sorting nexin 4) 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 associated with the long isoform of the leptin receptor and with receptor tyrosine kinases for platelet-derived growth factor, insulin, and epidermal growth factor in cell cultures, but its function is unknown. This protein may form oligomeric complexes with family members. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNX4	NM_003794.4	c.823G>A	p.Gly275Arg	missense_variant	Exon 9 of 14	ENST00000251775.9	NP_003785.1
SNX4	XM_017007414.3	c.919G>A	p.Gly307Arg	missense_variant	Exon 10 of 15		XP_016862903.1
SNX4	NR_073435.2	n.731G>A		non_coding_transcript_exon_variant	Exon 8 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNX4	ENST00000251775.9	c.823G>A	p.Gly275Arg	missense_variant	Exon 9 of 14	1	NM_003794.4	ENSP00000251775.4
SNX4	ENST00000471751.5	n.*551G>A		non_coding_transcript_exon_variant	Exon 8 of 13	2		ENSP00000420526.1
SNX4	ENST00000473417.5	n.713G>A		non_coding_transcript_exon_variant	Exon 7 of 7	3
SNX4	ENST00000471751.5	n.*551G>A		3_prime_UTR_variant	Exon 8 of 13	2		ENSP00000420526.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.823G>A (p.G275R) alteration is located in exon 9 (coding exon 9) of the SNX4 gene. This alteration results from a G to A substitution at nucleotide position 823, causing the glycine (G) at amino acid position 275 to be replaced by an arginine (R). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.087	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.32		Loss of catalytic residue at Q277 (P = 0.0859);
MVP		0.86
MPC		0.50
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.39
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-125188329;