NM_004247.4:c.1732C>T

Variant names:

• chr17-44860033-G-A
• rs1057520673
• NM_004247.4:c.1732C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004247.4(EFTUD2):​c.1732C>T​(p.Arg578*) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFTUD2 NM_004247.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.72

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44860033-G-A is Pathogenic according to our data. Variant chr17-44860033-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 379625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44860033-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFTUD2	NM_004247.4	c.1732C>T	p.Arg578*	stop_gained	Exon 18 of 28	ENST00000426333.7	NP_004238.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFTUD2	ENST00000426333.7	c.1732C>T	p.Arg578*	stop_gained	Exon 18 of 28	1	NM_004247.4	ENSP00000392094.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jan 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect consistent with a loss of function (Thomas et al., 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25735261, 25326635, 27670155, 26507355, 32333448) -

Mandibulofacial dysostosis-microcephaly syndrome Pathogenic:1

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory de novo in a 2-year-old male with microcephaly, ear malformations, hearin loss, PFO, cryptorchidism -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	52
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.93
GERP RS		4.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -12

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057520673; hg19: chr17-42937401; COSMIC: COSV68182136; COSMIC: COSV68182136;