rs372039780

Variant names:

• chr4-4420051-C-A
• rs372039780
• NM_016930.4:c.991G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-4420051-C-A
• chr4-4420051-C-G
• chr4-4420051-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016930.4(STX18):​c.991G>T​(p.Asp331Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D331H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STX18 NM_016930.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.23
• Publications: 0 publications found

Genes affected

STX18 (HGNC:15942): (syntaxin 18) This gene encodes a member of the syntaxin family of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) which is part of a membrane tethering complex that includes other SNAREs and several peripheral membrane proteins, and is involved in vesicular transport between the endoplasmic reticulum (ER) and the Golgi complex. The encoded protein is important for the organization of the smooth, rough, and exit site ER subdomains. A pseudogene of this gene has been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016930.4. 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
	STX18	NM_016930.4	MANE Select	c.991G>T	p.Asp331Tyr	missense	Exon 11 of 11	NP_058626.1	Q9P2W9
	STX18	NM_001346281.2		c.985G>T	p.Asp329Tyr	missense	Exon 11 of 11	NP_001333210.1
	STX18	NM_001346282.2		c.748G>T	p.Asp250Tyr	missense	Exon 11 of 11	NP_001333211.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STX18	ENST00000306200.7	TSL:1 MANE Select	c.991G>T	p.Asp331Tyr	missense	Exon 11 of 11	ENSP00000305810.2	Q9P2W9
	STX18	ENST00000505286.5	TSL:1	c.912+813G>T		intron	N/A	ENSP00000426648.1	D6RF48
	STX18	ENST00000503692.5	TSL:1	n.2414G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460318 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726260

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111338

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.80		Loss of disorder (P = 0.0174)
MVP		0.72
MPC		0.96
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.98
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372039780; hg19: chr4-4421778;