4-185323589-T-C

Position:

• chr4-185323589-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378034.2(SNX25):​c.1538T>C​(p.Ile513Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,956 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SNX25 NM_001378034.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX25	NM_001378034.2	c.1538T>C	p.Ile513Thr	missense_variant	9/19	ENST00000652585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX25	ENST00000652585.2	c.1538T>C	p.Ile513Thr	missense_variant	9/19		NM_001378034.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460956 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726792

Gnomad4 AFR exome AF: 0.0000897

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1046T>C (p.I349T) alteration is located in exon 9 (coding exon 8) of the SNX25 gene. This alteration results from a T to C substitution at nucleotide position 1046, causing the isoleucine (I) at amino acid position 349 to be replaced by a threonine (T). 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	0.84
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.75
MutPred		0.72		.;Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);
MVP		0.40
MPC		0.70
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.77
gMVP		0.56

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: rs1457522064; hg19: chr4-186244743;