15-82240555-T-C

Variant names:

• chr15-82240555-T-C
• rs1441937959
• NM_024580.6:c.379A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_024580.6(EFL1):​c.379A>G​(p.Thr127Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,456,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: EFL1 NM_024580.6 missense, splice_region
• Scores: Splicing: ADA: 0.3205
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.45
• Publications: 6 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 15-82240555-T-C is Pathogenic according to our data. Variant chr15-82240555-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522819.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFL1	NM_024580.6	MANE Select	c.379A>G	p.Thr127Ala	missense splice_region	Exon 6 of 20	NP_078856.4
	EFL1	NM_001322845.2		c.379A>G	p.Thr127Ala	missense splice_region	Exon 6 of 20	NP_001309774.1
	EFL1	NM_001040610.3		c.226A>G	p.Thr76Ala	missense splice_region	Exon 4 of 18	NP_001035700.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFL1	ENST00000268206.12	TSL:1 MANE Select	c.379A>G	p.Thr127Ala	missense splice_region	Exon 6 of 20	ENSP00000268206.7
	EFL1	ENST00000359445.8	TSL:1	c.226A>G	p.Thr76Ala	missense splice_region	Exon 4 of 18	ENSP00000352418.3
	EFL1	ENST00000696330.1		c.379A>G	p.Thr127Ala	missense splice_region	Exon 6 of 20	ENSP00000512564.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000822 AC: 2 AN: 243402 AF XY: 0.00000758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1456990 Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 6 AN XY: 724540

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 43314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 84740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110828

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Shwachman-Diamond syndrome 2 Pathogenic:2

Apr 18, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 18, 2018

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This individual has been reported in PMID: 29970384.

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.Thr127Ala variant in EFL1 has been reported, in the homozygous state, in 1 individual with Shwachman-Diamond syndrome (PMID: 29970384), and has been identified in 0.0006% (7/1110828) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1441937959). 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 also been reported in ClinVar (Variation ID: 522819) and has been interpreted as likely pathogenic by Undiagnosed Diseases Network (NIH) and pathogenic by OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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.Thr127Ala variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.77	D
PhyloP100		7.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at T127 (P = 0.1257)
MVP		0.89
MPC		0.77
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.88
gMVP		0.82
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.32
dbscSNV1_RF	Benign	0.70
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: rs1441937959; hg19: chr15-82532896;