15-82130503-C-T

Position:

• chr15-82130503-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024580.6(EFL1):​c.3233G>A​(p.Gly1078Glu) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFL1 NM_024580.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.64

Genes affected

EFL1 (HGNC:25789): (elongation factor like GTPase 1) Enables GTPase activity and ribosome binding activity. Involved in GTP metabolic process and mature ribosome assembly. Predicted to be part of ribonucleoprotein complex. Implicated in Shwachman-Diamond syndrome. [provided by Alliance of Genome Resources, Apr 2022]

EFL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFL1	NM_024580.6	c.3233G>A	p.Gly1078Glu	missense_variant	20/20	ENST00000268206.12	NP_078856.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFL1	ENST00000268206.12	c.3233G>A	p.Gly1078Glu	missense_variant	20/20	1	NM_024580.6	ENSP00000268206.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.3233G>A (p.G1078E) alteration is located in exon 20 (coding exon 19) of the EFL1 gene. This alteration results from a G to A substitution at nucleotide position 3233, causing the glycine (G) at amino acid position 1078 to be replaced by a glutamic acid (E). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the EFL1 c.3233G>A alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G1078 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.G1078E alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2021

ClinVar contains an entry for this variant (Variation ID: 985048). This variant has not been reported in the literature in individuals affected with EFL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1078 of the EFL1 protein (p.Gly1078Glu). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.43	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.36		Gain of disorder (P = 0.0503);.;
MVP		0.85
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs2073628340; hg19: chr15-82422844;