rs61762678

Positions:

• chr1-151665993-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001330723.2(SNX27):​c.967G>A​(p.Val323Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,611,398 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (15 hom.)
• Consequence: SNX27 NM_001330723.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010459214).
• BP6: Variant 1-151665993-G-A is Benign according to our data. Variant chr1-151665993-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0029 (442/152330) while in subpopulation NFE AF= 0.00435 (296/68030). AF 95% confidence interval is 0.00394. There are 2 homozygotes in gnomad4. There are 241 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 442 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNX27	NM_001330723.2	c.967G>A	p.Val323Met	missense_variant	6/12	ENST00000458013.7	NP_001317652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNX27	ENST00000458013.7	c.967G>A	p.Val323Met	missense_variant	6/12	5	NM_001330723.2	ENSP00000400333	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152212 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00316 AC: 790 AN: 249942 Hom.: 3 AF XY: 0.00319 AC XY: 431 AN XY: 135140

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00759

Gnomad NFE exome AF: 0.00509

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00334 AC: 4879 AN: 1459068 Hom.: 15 Cov.: 29 AF XY: 0.00326 AC XY: 2365 AN XY: 725828

Gnomad4 AFR exome AF: 0.000629

Gnomad4 AMR exome AF: 0.000292

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00802

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152330 Hom.: 2 Cov.: 32 AF XY: 0.00324 AC XY: 241 AN XY: 74494

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00932

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00364 Hom.: 4

Bravo AF: 0.00203

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00363 AC: 441

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

SNX27-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Severe myoclonic epilepsy in infancy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.0	.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.88	.;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.35	.;T;T
Sift4G	Benign	0.49	.;T;T
Polyphen		0.20, 0.24	.;B;B
Vest4		0.86, 0.85
MVP		0.85
MPC		0.68
ClinPred		0.021	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.61

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: rs61762678; hg19: chr1-151638469;