rs886037918

Variant names:

• chr20-46370526-C-G
• rs886037918
• NM_133171.5:c.1802-1G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_133171.5(ELMO2):​c.1802-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELMO2 NM_133171.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.61
• Publications: 0 publications found

Genes affected

ELMO2 (HGNC:17233): (engulfment and cell motility 2) The protein encoded by this gene interacts with the dedicator of cyto-kinesis 1 protein. Similarity to a C. elegans protein suggests that this protein may function in phagocytosis of apoptotic cells and in cell migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ELMO2 Gene-Disease associations (from GenCC):

• primary intraosseous venous malformation

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Ramon syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000273828 (HGNC:):

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.038372632 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 12, new splice context is: tttatcacttcctgttgcAGaca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-46370526-C-G is Pathogenic according to our data. Variant chr20-46370526-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 254192.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133171.5. 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
	ELMO2	NM_133171.5	MANE Select	c.1802-1G>C		splice_acceptor intron	N/A	NP_573403.1
	ELMO2	NM_182764.3		c.1802-1G>C		splice_acceptor intron	N/A	NP_877496.1
	ELMO2	NM_001318253.2		c.1538-1G>C		splice_acceptor intron	N/A	NP_001305182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELMO2	ENST00000290246.11	TSL:1 MANE Select	c.1802-1G>C		splice_acceptor intron	N/A	ENSP00000290246.6
	ELMO2	ENST00000396391.5	TSL:1	c.1802-1G>C		splice_acceptor intron	N/A	ENSP00000379673.1
	ELMO2	ENST00000372176.5	TSL:5	c.1538-1G>C		splice_acceptor intron	N/A	ENSP00000361249.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Primary intraosseous venous malformation (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.6
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: -13
DS_AL_spliceai		0.87		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037918; hg19: chr20-44999165;