7-2256945-G-A

Variant names:

• chr7-2256945-G-A
• rs1562419133
• NM_013321.4:c.1213C>T

Variant summary

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

The NM_013321.4(SNX8):​c.1213C>T​(p.His405Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. H405D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SNX8 NM_013321.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33918822).

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.1213C>T	p.His405Tyr	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.1213C>T	p.His405Tyr	missense	Exon 10 of 11	ENSP00000222990.3	Q9Y5X2
	SNX8	ENST00000926983.1		c.1210C>T	p.His404Tyr	missense	Exon 10 of 11	ENSP00000597042.1
	SNX8	ENST00000878404.1		c.1204C>T	p.His402Tyr	missense	Exon 10 of 11	ENSP00000548463.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461270 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 726918

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111806

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0051	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.13	B
Vest4		0.50
MutPred		0.61		Gain of catalytic residue at I404 (P = 0.0617)
MVP		0.43
MPC		0.48
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.17
gMVP		0.56
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1562419133; hg19: chr7-2296580;