4-185346573-C-G

Position:

• chr4-185346573-C-G

Variant summary

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

The NM_001378034.2(SNX25):​c.2224C>G​(p.Leu742Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,808 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SNX25 NM_001378034.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35

Genes affected

SNX25 (HGNC:21883): (sorting nexin 25) Predicted to enable type I transforming growth factor beta receptor binding activity. Involved in negative regulation of pathway-restricted SMAD protein phosphorylation; negative regulation of transforming growth factor beta receptor signaling pathway; and receptor catabolic process. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

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=0.37093234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX25	NM_001378034.2	c.2224C>G	p.Leu742Val	missense_variant	13/19	ENST00000652585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX25	ENST00000652585.2	c.2224C>G	p.Leu742Val	missense_variant	13/19		NM_001378034.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444808 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000251

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 15, 2023

The c.1732C>G (p.L578V) alteration is located in exon 13 (coding exon 12) of the SNX25 gene. This alteration results from a C to G substitution at nucleotide position 1732, causing the leucine (L) at amino acid position 578 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.3	.;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.58	.;N;N
REVEL	Benign	0.17
Sift	Benign	0.43	.;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.42
MutPred		0.34		.;Gain of MoRF binding (P = 0.1572);Gain of MoRF binding (P = 0.1572);
MVP		0.66
MPC		0.19
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.16
gMVP		0.27

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: chr4-186267727; COSMIC: COSV53015769;