1-151660857-G-C

Variant names:

• chr1-151660857-G-C
• rs779687444
• NM_001330723.2:c.796G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330723.2(SNX27):​c.796G>C​(p.Asp266His) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,114 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SNX27 NM_001330723.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.796G>C	p.Asp266His	missense	Exon 4 of 12	NP_001317652.1	Q96L92-1
	SNX27	NM_030918.6		c.796G>C	p.Asp266His	missense	Exon 4 of 12	NP_112180.4
	SNX27	NM_001437601.1		c.493G>C	p.Asp165His	missense	Exon 3 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.796G>C	p.Asp266His	missense	Exon 4 of 12	ENSP00000400333.2	Q96L92-1
	SNX27	ENST00000368843.8	TSL:1	c.796G>C	p.Asp266His	missense	Exon 4 of 12	ENSP00000357836.3	Q96L92-3
	SNX27	ENST00000368838.2	TSL:1	c.391G>C	p.Asp131His	missense	Exon 3 of 10	ENSP00000357831.2	A0A5H1ZRP6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456114 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106948

Other (OTH) AF: 0.00 AC: 0 AN: 60200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.83
MutPred		0.33		Gain of loop (P = 0.0851)
MVP		0.36
MPC		1.7
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.64
Mutation Taster		=31/69	disease causing

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: rs779687444; hg19: chr1-151633333;