rs1555565772

Variant names:

• chr17-44862750-T-C
• rs1555565772
• NM_004247.4:c.1570A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.40

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the EFTUD2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 4.0264 (above the threshold of 3.09). Trascript score misZ: 5.3556 (above the threshold of 3.09). GenCC associations: The gene is linked to mandibulofacial dysostosis-microcephaly syndrome.
• PP3: Splicing scoreres supports a deletorius 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 id is 521747.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFTUD2	NM_004247.4	c.1570A>G	p.Ile524Val	missense_variant	Exon 16 of 28	ENST00000426333.7	NP_004238.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFTUD2	ENST00000426333.7	c.1570A>G	p.Ile524Val	missense_variant	Exon 16 of 28	1	NM_004247.4	ENSP00000392094.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

May 09, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29565416, 19921636, 16760738, 22305528, 22541558, 22581936, 23188108, 23239648, 23879989, 24266672, 25735261, 25790162, 26118977, 26507355, 27670155, 24470203) -

Inborn genetic diseases Uncertain:1

Jun 22, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	26
DANN	Benign	0.67
DEOGEN2	Benign	0.15	T;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.040	N;.;N;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.13	N;.;.;N
REVEL	Benign	0.061
Sift	Benign	1.0	T;.;.;T
Sift4G	Benign	0.78	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.14
MutPred		0.40		Gain of disorder (P = 0.1136);.;Gain of disorder (P = 0.1136);.;
MVP		0.12
MPC		0.47
ClinPred		0.66	D
GERP RS		6.2
Varity_R		0.10
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs1555565772; hg19: chr17-42940118;