16-12048618-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032167.5(SNX29):c.746C>T(p.Ala249Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SNX29 NM_032167.5 missense, splice_region
• Scores: Splicing: ADA: 0.01435
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

SNX29 (HGNC:30542): (sorting nexin 29) Predicted to enable phosphatidylinositol binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118305475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX29	NM_032167.5	c.746C>T	p.Ala249Val	missense_variant, splice_region_variant	7/21	ENST00000566228.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX29	ENST00000566228.6	c.746C>T	p.Ala249Val	missense_variant, splice_region_variant	7/21	5	NM_032167.5	P1
SNX29	ENST00000564111.5	n.808C>T		splice_region_variant, non_coding_transcript_exon_variant	7/8	2
SNX29	ENST00000568359.1	n.577C>T		splice_region_variant, non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461670 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

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

Jun 03, 2022

The c.746C>T (p.A249V) alteration is located in exon 1 (coding exon 1) of the SNX29 gene. This alteration results from a C to T substitution at nucleotide position 746, causing the alanine (A) at amino acid position 249 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	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.69	N
Sift	Benign	0.19	T
Sift4G	Benign	0.28	T
Vest4		0.13
MVP		0.36
ClinPred		0.063	T
GERP RS		-1.8
Varity_R		0.035
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.27
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

LitVar

Other links and lift over

dbSNP: rs759295478; hg19: chr16-12142475;