7-2257418-C-A

Position:

• chr7-2257418-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013321.4(SNX8):​c.1081G>T​(p.Ala361Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A361T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SNX8 NM_013321.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11105928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNX8	NM_013321.4	c.1081G>T	p.Ala361Ser	missense_variant	9/11	ENST00000222990.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNX8	ENST00000222990.8	c.1081G>T	p.Ala361Ser	missense_variant	9/11	1	NM_013321.4	P1
SNX8	ENST00000480807.1	n.201G>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458332 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1081G>T (p.A361S) alteration is located in exon 9 (coding exon 9) of the SNX8 gene. This alteration results from a G to T substitution at nucleotide position 1081, causing the alanine (A) at amino acid position 361 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.88	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.042
Sift	Benign	0.42	T
Sift4G	Benign	0.44	T
Polyphen		0.063	B
Vest4		0.16
MutPred		0.19		Gain of phosphorylation at A361 (P = 0.0343);
MVP		0.25
MPC		0.28
ClinPred		0.26	T
GERP RS		4.1
Varity_R		0.033
gMVP		0.13

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-2297053;