rs138647604

Variant names:

• chr20-58669353-G-T
• rs138647604
• NM_001001433.3:c.456G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001001433.3(STX16):​c.456G>T​(p.Glu152Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,612,058 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E152Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (2 hom.)
• Consequence: STX16 NM_001001433.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.03
• Publications: 3 publications found

Genes affected

STX16 (HGNC:11431): (syntaxin 16) This gene encodes a protein that is a member of the syntaxin or t-SNARE (target-SNAP receptor) family. These proteins are found on cell membranes and serve as the targets for V-SNARES (vesicle-SNAP receptors) permitting specific synaptic vesicle docking and fusion. A microdeletion in the region of chromosome 20 where this gene is located has been associated with pseudohypoparathyroidism type Ib. Multiple transcript variants have been found for this gene. Read-through transcription also exists between this gene and the neighboring downstream aminopeptidase-like 1 (NPEPL1) gene. [provided by RefSeq, Mar 2011]

STX16-NPEPL1 (HGNC:41993): (STX16-NPEPL1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring syntaxin 16 (STX16) and aminopeptidase-like 1 (NPEPL1) genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008934915).
• BP6: Variant 20-58669353-G-T is Benign according to our data. Variant chr20-58669353-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 339049.
• BS2: High AC in GnomAd4 at 147 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001433.3. 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
	STX16	NM_001001433.3	MANE Select	c.456G>T	p.Glu152Asp	missense	Exon 5 of 9	NP_001001433.1	O14662-1
	STX16	NM_001134772.3		c.444G>T	p.Glu148Asp	missense	Exon 4 of 8	NP_001128244.1	O14662-5
	STX16	NM_001134773.3		c.405G>T	p.Glu135Asp	missense	Exon 5 of 9	NP_001128245.1	O14662-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX16	ENST00000371141.8	TSL:2 MANE Select	c.456G>T	p.Glu152Asp	missense	Exon 5 of 9	ENSP00000360183.4	O14662-1
	STX16	ENST00000358029.8	TSL:1	c.444G>T	p.Glu148Asp	missense	Exon 4 of 8	ENSP00000350723.4	O14662-5
	STX16	ENST00000371132.8	TSL:1	c.393G>T	p.Glu131Asp	missense	Exon 4 of 8	ENSP00000360173.4	O14662-2

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152194 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00120 AC: 293 AN: 245002 AF XY: 0.00120

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000962 AC: 1405 AN: 1459746 Hom.: 2 Cov.: 30 AF XY: 0.000968 AC XY: 703 AN XY: 726248

African (AFR) AF: 0.000239 AC: 8 AN: 33434

American (AMR) AF: 0.000471 AC: 21 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 327 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86162

European-Finnish (FIN) AF: 0.0000380 AC: 2 AN: 52610

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5752

European-Non Finnish (NFE) AF: 0.000793 AC: 881 AN: 1111172

Other (OTH) AF: 0.00153 AC: 92 AN: 60308

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74476

African (AFR) AF: 0.000265 AC: 11 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00201 Hom.: 1

Bravo AF: 0.000960

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.00112 AC: 136

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00285

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	Pseudohypoparathyroidism type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
PhyloP100		1.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.099
Sift	Benign	0.40	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.37		Loss of disorder (P = 0.0932)
MVP		0.29
MPC		0.31
ClinPred		0.029	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.11
Mutation Taster		=99/1	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: rs138647604; hg19: chr20-57244409;