NM_001330723.2:c.1324G>A

Variant names:

• chr1-151692519-G-A
• rs149937418
• NM_001330723.2:c.1324G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001330723.2(SNX27):​c.1324G>A​(p.Val442Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000214 in 1,587,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SNX27 NM_001330723.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.98
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28557095).

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.1324G>A	p.Val442Ile	missense	Exon 9 of 12	NP_001317652.1	Q96L92-1
	SNX27	NM_030918.6		c.1324G>A	p.Val442Ile	missense	Exon 9 of 12	NP_112180.4
	SNX27	NM_001437601.1		c.1021G>A	p.Val341Ile	missense	Exon 8 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.1324G>A	p.Val442Ile	missense	Exon 9 of 12	ENSP00000400333.2	Q96L92-1
	SNX27	ENST00000368843.8	TSL:1	c.1324G>A	p.Val442Ile	missense	Exon 9 of 12	ENSP00000357836.3	Q96L92-3
	SNX27	ENST00000368838.2	TSL:1	c.919G>A	p.Val307Ile	missense	Exon 8 of 10	ENSP00000357831.2	A0A5H1ZRP6

Frequencies

GnomAD3 genomes AF: 0.0000345 AC: 5 AN: 144808 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000763

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: 0.0000299

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251448 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 29 AN: 1442224 Hom.: 0 Cov.: 35 AF XY: 0.00000976 AC XY: 7 AN XY: 717072

African (AFR) AF: 0.0000606 AC: 2 AN: 33006

American (AMR) AF: 0.00 AC: 0 AN: 44040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 38512

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000228 AC: 25 AN: 1098656

Other (OTH) AF: 0.00 AC: 0 AN: 59056

GnomAD4 genome AF: 0.0000345 AC: 5 AN: 144808 Hom.: 0 Cov.: 31 AF XY: 0.0000286 AC XY: 2 AN XY: 70018

African (AFR) AF: 0.0000763 AC: 3 AN: 39312

American (AMR) AF: 0.00 AC: 0 AN: 13716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 4716

South Asian (SAS) AF: 0.00 AC: 0 AN: 4412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000299 AC: 2 AN: 66844

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.0000565 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.38
Sift	Benign	0.063	T
Sift4G	Benign	0.13	T
Polyphen		0.25	B
Vest4		0.63
MVP		0.49
MPC		0.48
ClinPred		0.18	T
GERP RS		6.0
Varity_R		0.072
gMVP		0.34
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs149937418; hg19: chr1-151664995; COSMIC: COSV64326903;