1-151612228-T-G

Position:

• chr1-151612228-T-G

Variant summary

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

The NM_001330723.2(SNX27):​c.27T>G​(p.Ile9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000805 in 1,241,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: SNX27 NM_001330723.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

SNX27 (HGNC:20073): (sorting nexin 27) This gene encodes a member of the sorting nexin family, a diverse group of cytoplasmic and membrane-associated proteins involved in endocytosis of plasma membrane receptors and protein trafficking through these compartments. All members of this protein family contain a phosphoinositide binding domain (PX domain). A highly similar protein in mouse is responsible for the specific recruitment of an isoform of serotonin 5-hydroxytryptamine 4 receptor into early endosomes, suggesting the analogous role for the human protein. [provided by RefSeq, Jul 2008]

(HGNC:):

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=0.18868077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX27	NM_001330723.2	c.27T>G	p.Ile9Met	missense_variant	1/12	ENST00000458013.7	NP_001317652.1
LOC124904420	XR_007066622.1	n.350A>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX27	ENST00000458013.7	c.27T>G	p.Ile9Met	missense_variant	1/12	5	NM_001330723.2	ENSP00000400333	P1
	ENST00000504583.2	n.345A>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.05e-7 AC: 1 AN: 1241476 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 604338

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.94e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000128 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe myoclonic epilepsy in infancy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 02, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with SNX27-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 9 of the SNX27 protein (p.Ile9Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Benign	0.87
DEOGEN2	Benign	0.076	.;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0080
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.020	.;N;N
REVEL	Benign	0.079
Sift	Benign	0.030	.;D;D
Sift4G	Benign	0.12	.;T;T
Polyphen		0.83	.;P;.
Vest4		0.20, 0.24
MutPred		0.15		Loss of catalytic residue at P11 (P = 0.0535);Loss of catalytic residue at P11 (P = 0.0535);Loss of catalytic residue at P11 (P = 0.0535);
MVP		0.50
MPC		0.69
ClinPred		0.39	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs766165959; hg19: chr1-151584704;