Genetic Variant ELMOD1:p.Arg39Trp (chr11-107630514-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018712.4(ELMOD1):c.115C>T(p.Arg39Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,610,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ELMOD1
NM_018712.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

Variant links:

Genes affected

ELMOD1 (HGNC:25334): (ELMO domain containing 1) Enables GTPase activator activity. Predicted to be involved in positive regulation of GTPase activity. [provided by Alliance of Genome Resources, Apr 2022]

ELMOD1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELMOD1	NM_018712.4 link	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 12	ENST00000265840.12	NP_061182.3	Q8N336-1
ELMOD1	NM_001308018.2 link	c.97C>T	p.Arg33Trp	missense_variant	Exon 4 of 13		NP_001294947.1	Q8N336E9PLM8B4DM88
ELMOD1	NM_001130037.2 link	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 11		NP_001123509.1	Q8N336-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ELMOD1	ENST00000265840.12 link	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 12	1	NM_018712.4	ENSP00000265840.7	Q8N336-1
ELMOD1	ENST00000531234.5 link	c.97C>T	p.Arg33Trp	missense_variant	Exon 4 of 13	2		ENSP00000433232.1	E9PLM8
ELMOD1	ENST00000443271.2 link	c.115C>T	p.Arg39Trp	missense_variant	Exon 3 of 11	2		ENSP00000412257.2	Q8N336-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458218

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115C>T (p.R39W) alteration is located in exon 3 (coding exon 2) of the ELMOD1 gene. This alteration results from a C to T substitution at nucleotide position 115, causing the arginine (R) at amino acid position 39 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.1

.;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.94

MutPred

0.81

.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.55

MPC

0.50

ClinPred

1.0

GERP RS

3.5

Varity_R

0.86

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over