6-85508320-TAAAAAAAA-TAAAAAA

Variant names:

• chr6-85508320-TAA-T
• rs765165360
• NM_153816.6:c.2654-263_2654-262delTT

Variant summary

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

The NM_153816.6(SNX14):​c.2654-263_2654-262delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0961 in 698,020 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 31)
  • Exomes 𝑓: 0.096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNX14 NM_153816.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.883
• Publications: 0 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 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.103) population. However there is too low homozygotes in high coverage region: (expected more than 1612, got 0).

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.2654-263_2654-262delTT		intron	N/A	NP_722523.1	Q9Y5W7-1
	SNX14	NM_001350532.2		c.2717-263_2717-262delTT		intron	N/A	NP_001337461.1	A0A804HKZ1
	SNX14	NM_001350533.2		c.2651-263_2651-262delTT		intron	N/A	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.2654-263_2654-262delTT		intron	N/A	ENSP00000313121.3	Q9Y5W7-1
	SNX14	ENST00000369627.6	TSL:1	c.2627-263_2627-262delTT		intron	N/A	ENSP00000358641.2	Q9Y5W7-4
	SNX14	ENST00000346348.7	TSL:1	c.2495-263_2495-262delTT		intron	N/A	ENSP00000257769.3	Q9Y5W7-2

Frequencies

GnomAD3 genomes AF: 0.000839 AC: 83 AN: 98918 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000524

Gnomad SAS AF: 0.000305

Gnomad FIN AF: 0.00338

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000887

Gnomad OTH AF: 0.00149

GnomAD4 exome AF: 0.0961 AC: 67099 AN: 698020 Hom.: 0 AF XY: 0.0957 AC XY: 30983 AN XY: 323838

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

African (AFR) AF: 0.0898 AC: 1180 AN: 13144

American (AMR) AF: 0.116 AC: 133 AN: 1150

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 518 AN: 4684

East Asian (EAS) AF: 0.111 AC: 450 AN: 4046

South Asian (SAS) AF: 0.102 AC: 1409 AN: 13832

European-Finnish (FIN) AF: 0.133 AC: 127 AN: 956

Middle Eastern (MID) AF: 0.0874 AC: 126 AN: 1442

European-Non Finnish (NFE) AF: 0.0959 AC: 60943 AN: 635418

Other (OTH) AF: 0.0948 AC: 2213 AN: 23348

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000839 AC: 83 AN: 98896 Hom.: 0 Cov.: 31 AF XY: 0.00109 AC XY: 51 AN XY: 46912

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

African (AFR) AF: 0.000257 AC: 7 AN: 27186

American (AMR) AF: 0.00153 AC: 14 AN: 9146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2414

East Asian (EAS) AF: 0.000789 AC: 3 AN: 3802

South Asian (SAS) AF: 0.00 AC: 0 AN: 3246

European-Finnish (FIN) AF: 0.00338 AC: 16 AN: 4740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.000887 AC: 41 AN: 46218

Other (OTH) AF: 0.00148 AC: 2 AN: 1350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765165360; hg19: chr6-86218038;