chr3-125476734-C-T

Variant names:

• chr3-125476734-C-T
• rs1416426710
• NM_003794.4:c.749G>A

Variant summary

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

The NM_003794.4(SNX4):​c.749G>A​(p.Gly250Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,445,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SNX4 NM_003794.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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 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
SNX4	NM_003794.4	c.749G>A	p.Gly250Asp	missense_variant	Exon 8 of 14	ENST00000251775.9	NP_003785.1
SNX4	XM_017007414.3	c.749G>A	p.Gly250Asp	missense_variant	Exon 8 of 15		XP_016862903.1
SNX4	NR_073435.2	n.657G>A		non_coding_transcript_exon_variant	Exon 7 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNX4	ENST00000251775.9	c.749G>A	p.Gly250Asp	missense_variant	Exon 8 of 14	1	NM_003794.4	ENSP00000251775.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247046 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133500

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445558 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 719798

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.749G>A (p.G250D) alteration is located in exon 8 (coding exon 8) of the SNX4 gene. This alteration results from a G to A substitution at nucleotide position 749, causing the glycine (G) at amino acid position 250 to be replaced by an aspartic acid (D). 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	0.96
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.16
Sift	Benign	0.15	T
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.40		Loss of MoRF binding (P = 0.0725);
MVP		0.78
MPC		0.30
ClinPred		0.29	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs1416426710; hg19: chr3-125195578;