rs936843937

Variant names:

• chr6-85514180-C-T
• rs936843937
• NM_153816.6:c.2447G>A

Variant summary

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

The NM_153816.6(SNX14):​c.2447G>A​(p.Arg816Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SNX14 NM_153816.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 4 publications found

Genes affected

SNX14 (HGNC:14977): (sorting nexin 14) This gene encodes a member of the sorting nexin family. Members of this family have a phox (PX) phosphoinositide binding domain and are involved in intracellular trafficking. The encoded protein also contains a regulator of G protein signaling (RGS) domain. Regulator of G protein signaling family members are regulatory molecules that act as GTPase activating proteins for G alpha subunits of heterotrimeric G proteins. Alternate splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

SNX14 Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 20

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P, Ambry Genetics, PanelApp Australia

ENSG00000271793 (HGNC:):

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, 0.791

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153816.6. 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
	SNX14	NM_153816.6	MANE Select	c.2447G>A	p.Arg816Gln	missense	Exon 25 of 29	NP_722523.1	Q9Y5W7-1
	SNX14	NM_001350532.2		c.2510G>A	p.Arg837Gln	missense	Exon 26 of 30	NP_001337461.1	A0A804HKZ1
	SNX14	NM_001350533.2		c.2444G>A	p.Arg815Gln	missense	Exon 25 of 29	NP_001337462.1	A0A804HKC6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX14	ENST00000314673.8	TSL:1 MANE Select	c.2447G>A	p.Arg816Gln	missense	Exon 25 of 29	ENSP00000313121.3	Q9Y5W7-1
	SNX14	ENST00000369627.6	TSL:1	c.2420G>A	p.Arg807Gln	missense	Exon 24 of 28	ENSP00000358641.2	Q9Y5W7-4
	SNX14	ENST00000346348.7	TSL:1	c.2288G>A	p.Arg763Gln	missense	Exon 22 of 26	ENSP00000257769.3	Q9Y5W7-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39650

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111914

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive spinocerebellar ataxia 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.050	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Benign	0.082	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.85
MutPred		0.70		Loss of ubiquitination at K820 (P = 0.1016)
MVP		0.54
MPC		1.0
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.74
Mutation Taster		=65/35	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: rs936843937; hg19: chr6-86223898;