chr17-44853305-GC-G

Variant names:

• chr17-44853305-GC-G
• rs1555564126
• NM_004247.4:c.2551delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004247.4(EFTUD2):​c.2551delG​(p.Ala851ProfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFTUD2 NM_004247.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 17-44853305-GC-G is Pathogenic according to our data. Variant chr17-44853305-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488388.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFTUD2	NM_004247.4	c.2551delG	p.Ala851ProfsTer7	frameshift_variant	Exon 25 of 28	ENST00000426333.7	NP_004238.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFTUD2	ENST00000426333.7	c.2551delG	p.Ala851ProfsTer7	frameshift_variant	Exon 25 of 28	1	NM_004247.4	ENSP00000392094.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mandibulofacial dysostosis-microcephaly syndrome Pathogenic:1

Mar 31, 2017

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous deletion variant was identified, NM_004247.3(EFTUD2):c.2551delG in exon 25 of the EFTUD2 gene (chr17:42930673). This deletion is predicted to cause a frameshift from amino acid position 851, introducing a stop codon 7 residues downstream, NP_004238.3(EFTUD2):p.(Ala851ProfsTer7), resulting in loss of normal protein function either through truncation (loss of ~1/10th of the protien) or nonsense-mediated decay. This variant has not been previously observed in our cohort, it is not present in population databases (ExAC/GnomAD) and has not been previously observed in other clinical cases. However, other heterozygous truncating variants downstream of c.2551delG in EFTUD2 gene have been reported as pathogenic in individuals with Mandibulofacial dysostosis (ClinVar). Based on current information, this variant has been classified as LIKELY PATHOGENIC. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555564126; hg19: chr17-42930673;