rs61762678

Variant names:

• chr1-151665993-G-A
• rs61762678
• NM_001330723.2:c.967G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 9.07
• Publications: 7 publications found

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]

SNX27 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330723.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX27	NM_001330723.2	MANE Select	c.967G>A	p.Val323Met	missense	Exon 6 of 12	NP_001317652.1	Q96L92-1
	SNX27	NM_030918.6		c.967G>A	p.Val323Met	missense	Exon 6 of 12	NP_112180.4
	SNX27	NM_001437601.1		c.664G>A	p.Val222Met	missense	Exon 5 of 11	NP_001424530.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX27	ENST00000458013.7	TSL:5 MANE Select	c.967G>A	p.Val323Met	missense	Exon 6 of 12	ENSP00000400333.2	Q96L92-1
	SNX27	ENST00000368843.8	TSL:1	c.967G>A	p.Val323Met	missense	Exon 6 of 12	ENSP00000357836.3	Q96L92-3
	SNX27	ENST00000368838.2	TSL:1	c.562G>A	p.Val188Met	missense	Exon 5 of 10	ENSP00000357831.2	A0A5H1ZRP6

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

GnomAD2 exomes AF: 0.00316 AC: 790 AN: 249942 AF XY: 0.00319

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 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

African (AFR) AF: 0.000629 AC: 21 AN: 33408

American (AMR) AF: 0.000292 AC: 13 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85848

European-Finnish (FIN) AF: 0.00802 AC: 428 AN: 53334

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00383 AC: 4253 AN: 1110222

Other (OTH) AF: 0.00264 AC: 159 AN: 60274

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

African (AFR) AF: 0.000842 AC: 35 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00932 AC: 99 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68030

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00350 Hom.: 13

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Severe myoclonic epilepsy in infancy (1)
-	-	1	SNX27-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.0	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.42
Sift	Benign	0.35	T
Sift4G	Benign	0.49	T
Polyphen		0.20	B
Vest4		0.86
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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs61762678; hg19: chr1-151638469;