1-151612217-G-C

Variant names:

• chr1-151612217-G-C
• rs1027134476
• NM_001330723.2:c.16G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001330723.2(SNX27):​c.16G>C​(p.Gly6Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000515 in 1,359,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SNX27 NM_001330723.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.38

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]

ENSG00000250734 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNX27	NM_001330723.2	c.16G>C	p.Gly6Arg	missense_variant	Exon 1 of 12	ENST00000458013.7	NP_001317652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNX27	ENST00000458013.7	c.16G>C	p.Gly6Arg	missense_variant	Exon 1 of 12	5	NM_001330723.2	ENSP00000400333.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000497 AC: 6 AN: 1206912 Hom.: 0 Cov.: 31 AF XY: 0.00000171 AC XY: 1 AN XY: 583934

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.0000593

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>C (p.G6R) alteration is located in exon 1 (coding exon 1) of the SNX27 gene. This alteration results from a G to C substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Severe myoclonic epilepsy in infancy Uncertain:1

Jun 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 6 of the SNX27 protein (p.Gly6Arg). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SNX27-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.81	.;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.010	.;D;D
Polyphen		0.98	.;D;.
Vest4		0.55, 0.55
MutPred		0.42		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.62
MPC		1.7
ClinPred		0.84	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.36
gMVP		0.68

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: rs1027134476; hg19: chr1-151584693;