15-82151809-A-T

Variant names:

• chr15-82151809-A-T
• rs1316615934
• NM_024580.6:c.2645T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024580.6(EFL1):​c.2645T>A​(p.Met882Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EFL1 NM_024580.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 8.86
• Publications: 5 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFL1	NM_024580.6	c.2645T>A	p.Met882Lys	missense_variant	Exon 18 of 20	ENST00000268206.12	NP_078856.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFL1	ENST00000268206.12	c.2645T>A	p.Met882Lys	missense_variant	Exon 18 of 20	1	NM_024580.6	ENSP00000268206.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249040 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 68 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Shwachman-Diamond syndrome 2 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 19, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Shwachman syndrome Uncertain:1

Jan 10, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Met882Lys variant in EFL1 has been reported, in the homozygous state, in 1 individual with Shwachman-Diamond syndrome, segregated with disease in 1 affected relative from the same family (PMID: 28331068), and has been identified in 0.004% (2/44718) of Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1316615934). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (Variation ID: 522583), and has been interpreted as pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Met882Lys variant may slightly impact protein function (PMID: 28331068). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Furthermore, although this gene has been reported in association with Shwachman-Diamond syndrome, it currently has moderate evidence for these associations. In summary, the clinical significance of the p.Met882Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.69	T
PhyloP100		8.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.59	P;P
Vest4		0.96
MutPred		0.60		Loss of sheet (P = 0.0181);.;
MVP		0.69
MPC		0.79
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.96
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs1316615934; hg19: chr15-82444150;