rs1135401812

Variant names:

• chr17-44859985-GCTCCA-G
• rs1135401812
• NM_004247.4:c.1775_1779delTGGAG

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.1775_1779delTGGAG​(p.Val592AlafsTer12) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFTUD2 NM_004247.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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 17-44859985-GCTCCA-G is Pathogenic according to our data. Variant chr17-44859985-GCTCCA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 431142.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFTUD2	NM_004247.4	MANE Select	c.1775_1779delTGGAG	p.Val592AlafsTer12	frameshift	Exon 18 of 28	NP_004238.3
	EFTUD2	NM_001258353.2		c.1775_1779delTGGAG	p.Val592AlafsTer12	frameshift	Exon 18 of 28	NP_001245282.1
	EFTUD2	NM_001258354.2		c.1745_1749delTGGAG	p.Val582AlafsTer12	frameshift	Exon 18 of 28	NP_001245283.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFTUD2	ENST00000426333.7	TSL:1 MANE Select	c.1775_1779delTGGAG	p.Val592AlafsTer12	frameshift	Exon 18 of 28	ENSP00000392094.1
	EFTUD2	ENST00000969864.1		c.1943_1947delTGGAG	p.Val648AlafsTer12	frameshift	Exon 18 of 28	ENSP00000639923.1
	EFTUD2	ENST00000880576.1		c.1775_1779delTGGAG	p.Val592AlafsTer12	frameshift	Exon 18 of 28	ENSP00000550635.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mandibulofacial dysostosis-microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1135401812; hg19: chr17-42937353;