3-121381436-G-A

Variant names:

• chr3-121381436-G-A
• rs17740066
• NM_001308330.2:c.2491G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001308330.2(STXBP5L):​c.2491G>A​(p.Val831Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 1,605,206 control chromosomes in the GnomAD database, including 8,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.079 (601 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7832 hom.)
• Consequence: STXBP5L NM_001308330.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.95

Genes affected

STXBP5L (HGNC:30757): (syntaxin binding protein 5L) The protein encoded by this gene is similar to syntaxin-binding protein 5 and contains ten N-terminal WD40 repeats, four variable region WD40 repeats, and a C-terminal R-SNARE domain. Studies of the orthologous proteins in mouse and rat have shown that the encoded protein may inhibit exocytosis in neurosecretory cells, and may negatively regulate the secretion of insulin. A missense variant in this gene is likely the cause of an infantile-onset neurodegenerative disorder diagnosed in two siblings of consanguineous parents. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033420622).
• BP6: Variant 3-121381436-G-A is Benign according to our data. Variant chr3-121381436-G-A is described in ClinVar as [Benign]. Clinvar id is 3056299.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-121381436-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STXBP5L	NM_001308330.2	c.2491G>A	p.Val831Ile	missense_variant	Exon 22 of 27	ENST00000471454.6	NP_001295259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STXBP5L	ENST00000471454.6	c.2491G>A	p.Val831Ile	missense_variant	Exon 22 of 27	2	NM_001308330.2	ENSP00000420019.1

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12043 AN: 151816 Hom.: 600 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0982

Gnomad EAS AF: 0.0551

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0878

GnomAD2 exomes AF: 0.0973 AC: 23355 AN: 240050 AF XY: 0.0934

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0511

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0991 AC: 143966 AN: 1453272 Hom.: 7832 Cov.: 34 AF XY: 0.0970 AC XY: 70149 AN XY: 723000

Gnomad4 AFR exome AF: 0.0147 AC: 484 AN: 32842

Gnomad4 AMR exome AF: 0.167 AC: 6963 AN: 41728

Gnomad4 ASJ exome AF: 0.102 AC: 2623 AN: 25796

Gnomad4 EAS exome AF: 0.0351 AC: 1388 AN: 39584

Gnomad4 SAS exome AF: 0.0511 AC: 4320 AN: 84580

Gnomad4 FIN exome AF: 0.122 AC: 6502 AN: 53330

Gnomad4 NFE exome AF: 0.104 AC: 115627 AN: 1109594

Gnomad4 Remaining exome AF: 0.0952 AC: 5721 AN: 60086

GnomAD4 genome AF: 0.0793 AC: 12047 AN: 151934 Hom.: 601 Cov.: 32 AF XY: 0.0789 AC XY: 5853 AN XY: 74214

Gnomad4 AFR AF: 0.0198 AC: 0.0198399 AN: 0.0198399

Gnomad4 AMR AF: 0.120 AC: 0.119861 AN: 0.119861

Gnomad4 ASJ AF: 0.0982 AC: 0.0982091 AN: 0.0982091

Gnomad4 EAS AF: 0.0554 AC: 0.0554049 AN: 0.0554049

Gnomad4 SAS AF: 0.0587 AC: 0.0587137 AN: 0.0587137

Gnomad4 FIN AF: 0.116 AC: 0.115837 AN: 0.115837

Gnomad4 NFE AF: 0.104 AC: 0.10368 AN: 0.10368

Gnomad4 OTH AF: 0.0878 AC: 0.0878443 AN: 0.0878443

Alfa AF: 0.0947 Hom.: 3572

Bravo AF: 0.0788

TwinsUK AF: 0.0982 AC: 364

ALSPAC AF: 0.102 AC: 393

ESP6500AA AF: 0.0208 AC: 79

ESP6500EA AF: 0.108 AC: 890

ExAC AF: 0.0928 AC: 11216

Asia WGS AF: 0.0830 AC: 290 AN: 3478

EpiCase AF: 0.0958

EpiControl AF: 0.0969

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

STXBP5L-related disorder Benign:1

Apr 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;T;T;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
MetaRNN	Benign	0.0033	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.52	N;N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.33	T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.45
MPC		0.38
ClinPred		0.015	T
GERP RS		5.1
Varity_R		0.081
gMVP		0.36
Mutation Taster		=94/6	polymorphism (auto)

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

LitVar

Other links and lift over

dbSNP: rs17740066; hg19: chr3-121100283; COSMIC: COSV56510614;