chr3-121381436-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_014980.3(STXBP5L):​c.2563G>A​(p.Val855Ile) 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_014980.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.95
• Publications: 29 publications found

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 VariationId is 3056299.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014980.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5L	NM_001308330.2	MANE Select	c.2491G>A	p.Val831Ile	missense	Exon 22 of 27	NP_001295259.1
	STXBP5L	NM_001348343.2		c.2563G>A	p.Val855Ile	missense	Exon 23 of 28	NP_001335272.1
	STXBP5L	NM_014980.3		c.2563G>A	p.Val855Ile	missense	Exon 23 of 28	NP_055795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STXBP5L	ENST00000471454.6	TSL:2 MANE Select	c.2491G>A	p.Val831Ile	missense	Exon 22 of 27	ENSP00000420019.1
	STXBP5L	ENST00000273666.10	TSL:1	c.2563G>A	p.Val855Ile	missense	Exon 23 of 28	ENSP00000273666.6
	STXBP5L	ENST00000707001.1		c.2563G>A	p.Val855Ile	missense	Exon 23 of 28	ENSP00000516710.1

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

African (AFR) AF: 0.0147 AC: 484 AN: 32842

American (AMR) AF: 0.167 AC: 6963 AN: 41728

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2623 AN: 25796

East Asian (EAS) AF: 0.0351 AC: 1388 AN: 39584

South Asian (SAS) AF: 0.0511 AC: 4320 AN: 84580

European-Finnish (FIN) AF: 0.122 AC: 6502 AN: 53330

Middle Eastern (MID) AF: 0.0590 AC: 338 AN: 5732

European-Non Finnish (NFE) AF: 0.104 AC: 115627 AN: 1109594

Other (OTH) 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

African (AFR) AF: 0.0198 AC: 823 AN: 41482

American (AMR) AF: 0.120 AC: 1825 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.0982 AC: 340 AN: 3462

East Asian (EAS) AF: 0.0554 AC: 286 AN: 5162

South Asian (SAS) AF: 0.0587 AC: 283 AN: 4820

European-Finnish (FIN) AF: 0.116 AC: 1220 AN: 10532

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7044 AN: 67940

Other (OTH) AF: 0.0878 AC: 185 AN: 2106

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	STXBP5L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.097
Sift	Benign	0.33	T
Sift4G	Benign	0.50	T
Polyphen		1.0	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

Other links and lift over

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