NM_153260.3:c.658G>C

Variant names:

• chr15-42545097-C-G
• rs1356882850
• NM_153260.3:c.658G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153260.3(LRRC57):​c.658G>C​(p.Glu220Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,447,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LRRC57 NM_153260.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

LRRC57 (HGNC:26719): (leucine rich repeat containing 57) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285942 (HGNC:):

SNAP23 (HGNC:11131): (synaptosome associated protein 23) Specificity of vesicular transport is regulated, in part, by the interaction of a vesicle-associated membrane protein termed synaptobrevin/VAMP with a target compartment membrane protein termed syntaxin. These proteins, together with SNAP25 (synaptosome-associated protein of 25 kDa), form a complex which serves as a binding site for the general membrane fusion machinery. Synaptobrevin/VAMP and syntaxin are believed to be involved in vesicular transport in most, if not all cells, while SNAP25 is present almost exclusively in the brain, suggesting that a ubiquitously expressed homolog of SNAP25 exists to facilitate transport vesicle/target membrane fusion in other tissues. The protein encoded by this gene is structurally and functionally similar to SNAP25 and binds tightly to multiple syntaxins and synaptobrevins/VAMPs. It is an essential component of the high affinity receptor for the general membrane fusion machinery and is an important regulator of transport vesicle docking and fusion. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31541896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153260.3. 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
	LRRC57	NM_153260.3	MANE Select	c.658G>C	p.Glu220Gln	missense	Exon 5 of 6	NP_694992.2	Q8N9N7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC57	ENST00000397130.8	TSL:1 MANE Select	c.658G>C	p.Glu220Gln	missense	Exon 5 of 6	ENSP00000380319.3	Q8N9N7
	LRRC57	ENST00000323443.6	TSL:1	c.658G>C	p.Glu220Gln	missense	Exon 4 of 5	ENSP00000326817.2	Q8N9N7
	ENSG00000285942	ENST00000650210.1		n.658G>C		non_coding_transcript_exon	Exon 5 of 9	ENSP00000497618.1	A0A3B3ISV5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 237160 AF XY: 0.00000778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1447694 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 10 AN XY: 720140

African (AFR) AF: 0.00 AC: 0 AN: 32248

American (AMR) AF: 0.00 AC: 0 AN: 41528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25544

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 83816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1106688

Other (OTH) AF: 0.0000167 AC: 1 AN: 59766

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.061
Sift	Benign	0.14	T
Sift4G	Benign	0.37	T
Polyphen		0.13	B
Vest4		0.35
MutPred		0.47		Loss of ubiquitination at K217 (P = 0.0992)
MVP		0.76
MPC		0.36
ClinPred		0.35	T
GERP RS		5.6
Varity_R		0.24
gMVP		0.39
Mutation Taster		=73/27	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: rs1356882850; hg19: chr15-42837295;