chr4-185288013-T-C

Position:

• chr4-185288013-T-C

Variant summary

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

The NM_001378034.2(SNX25):​c.1093T>C​(p.Tyr365His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNX25 NM_001378034.2 missense, splice_region
• Scores: Splicing: ADA: 0.7925
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX25	NM_001378034.2	c.1093T>C	p.Tyr365His	missense_variant, splice_region_variant	6/19	ENST00000652585.2	NP_001364963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX25	ENST00000652585.2	c.1093T>C	p.Tyr365His	missense_variant, splice_region_variant	6/19		NM_001378034.2	ENSP00000498676
SNX25	ENST00000504273.5	c.601T>C	p.Tyr201His	missense_variant, splice_region_variant	6/19	1		ENSP00000426255	P1
SNX25	ENST00000264694.13	c.601T>C	p.Tyr201His	missense_variant, splice_region_variant	6/19	5		ENSP00000264694	P1
SNX25	ENST00000618785.4	c.-87T>C		splice_region_variant, 5_prime_UTR_variant	6/18	5		ENSP00000483653

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

The c.601T>C (p.Y201H) alteration is located in exon 6 (coding exon 5) of the SNX25 gene. This alteration results from a T to C substitution at nucleotide position 601, causing the tyrosine (Y) at amino acid position 201 to be replaced by a histidine (H). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.39		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.40
MPC		0.75
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.67
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.010		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: chr4-186209167;