Genetic Variant NM_004247.4:c.1570A>G (chr17-44862750-T-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_004247.4(EFTUD2):c.1570A>G(p.Ile524Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

EFTUD2
NM_004247.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.40

Publications

0 publications found

Variant links:

Genes affected

EFTUD2 (HGNC:30858): (elongation factor Tu GTP binding domain containing 2) This gene encodes a GTPase which is a component of the spliceosome complex which processes precursor mRNAs to produce mature mRNAs. Mutations in this gene are associated with mandibulofacial dysostosis with microcephaly. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

EFTUD2 Gene-Disease associations (from GenCC):

mandibulofacial dysostosis-microcephaly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

EFTUD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-44862750-T-C is Pathogenic according to our data. Variant chr17-44862750-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521747.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004247.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFTUD2	NM_004247.4	MANE Select	c.1570A>G	p.Ile524Val	missense	Exon 16 of 28	NP_004238.3
EFTUD2	NM_001258353.2		c.1570A>G	p.Ile524Val	missense	Exon 16 of 28	NP_001245282.1	Q15029-1
EFTUD2	NM_001258354.2		c.1540A>G	p.Ile514Val	missense	Exon 16 of 28	NP_001245283.1	Q15029-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFTUD2	ENST00000426333.7	TSL:1 MANE Select	c.1570A>G	p.Ile524Val	missense	Exon 16 of 28	ENSP00000392094.1	Q15029-1
EFTUD2	ENST00000969864.1		c.1570A>G	p.Ile524Val	missense	Exon 16 of 28	ENSP00000639923.1
EFTUD2	ENST00000880576.1		c.1570A>G	p.Ile524Val	missense	Exon 16 of 28	ENSP00000550635.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Pathogenic

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.15

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0064

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.040

PhyloP100

2.4

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.13

REVEL

Benign

0.061

Sift

Benign

1.0

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.14

MutPred

0.40

Gain of disorder (P = 0.1136)

MVP

0.12

MPC

0.47

ClinPred

0.66

GERP RS

6.2

Varity_R

0.10

gMVP

0.14

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: 1

DS_DL_spliceai

0.74

Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over