15-82130503-C-T

Variant names:

• chr15-82130503-C-T
• rs2073628340
• NM_024580.6:c.3233G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G1078G) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Shwachman-Diamond syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Shwachman-Diamond syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024580.6. 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
	EFL1	NM_024580.6	MANE Select	c.3233G>A	p.Gly1078Glu	missense	Exon 20 of 20	NP_078856.4
	EFL1	NM_001322845.2		c.3233G>A	p.Gly1078Glu	missense	Exon 20 of 20	NP_001309774.1	Q7Z2Z2-1
	EFL1	NM_001040610.3		c.3080G>A	p.Gly1027Glu	missense	Exon 18 of 18	NP_001035700.1	Q7Z2Z2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFL1	ENST00000268206.12	TSL:1 MANE Select	c.3233G>A	p.Gly1078Glu	missense	Exon 20 of 20	ENSP00000268206.7	Q7Z2Z2-1
	EFL1	ENST00000359445.8	TSL:1	c.3080G>A	p.Gly1027Glu	missense	Exon 18 of 18	ENSP00000352418.3	Q7Z2Z2-2
	EFL1	ENST00000956176.1		c.3329G>A	p.Gly1110Glu	missense	Exon 21 of 21	ENSP00000626235.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.43	D
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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

Other links and lift over

dbSNP: rs2073628340; hg19: chr15-82422844;