7-2256980-G-A

Variant names:

• chr7-2256980-G-A
• rs766575430
• NM_013321.4:c.1178C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013321.4(SNX8):​c.1178C>T​(p.Ser393Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S393Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SNX8 NM_013321.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.47
• Publications: 0 publications found

Genes affected

SNX8 (HGNC:14972): (sorting nexin 8) Enables identical protein binding activity and phosphatidylinositol binding activity. Involved in early endosome to Golgi transport and intracellular protein transport. Located in early endosome membrane. Colocalizes with retromer complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013321.4. 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
	SNX8	NM_013321.4	MANE Select	c.1178C>T	p.Ser393Phe	missense	Exon 10 of 11	NP_037453.1	Q9Y5X2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX8	ENST00000222990.8	TSL:1 MANE Select	c.1178C>T	p.Ser393Phe	missense	Exon 10 of 11	ENSP00000222990.3	Q9Y5X2
	SNX8	ENST00000926983.1		c.1175C>T	p.Ser392Phe	missense	Exon 10 of 11	ENSP00000597042.1
	SNX8	ENST00000878404.1		c.1169C>T	p.Ser390Phe	missense	Exon 10 of 11	ENSP00000548463.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460784 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726608

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111506

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.61	P
Vest4		0.90
MutPred		0.51		Loss of catalytic residue at S393 (P = 0.1154)
MVP		0.61
MPC		0.91
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.71
Mutation Taster		=21/79	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: rs766575430; hg19: chr7-2296615;