rs1057518932

Variant names:

• chr17-44855003-T-A
• rs1057518932
• NM_004247.4:c.2047A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_004247.4(EFTUD2):​c.2047A>T​(p.Asn683Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFTUD2 NM_004247.4 missense, splice_region
• Scores: Splicing: ADA: 0.9250
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 17-44855003-T-A is Pathogenic according to our data. Variant chr17-44855003-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374152.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFTUD2	NM_004247.4	MANE Select	c.2047A>T	p.Asn683Tyr	missense splice_region	Exon 21 of 28	NP_004238.3
	EFTUD2	NM_001258353.2		c.2047A>T	p.Asn683Tyr	missense splice_region	Exon 21 of 28	NP_001245282.1
	EFTUD2	NM_001258354.2		c.2017A>T	p.Asn673Tyr	missense splice_region	Exon 21 of 28	NP_001245283.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFTUD2	ENST00000426333.7	TSL:1 MANE Select	c.2047A>T	p.Asn683Tyr	missense splice_region	Exon 21 of 28	ENSP00000392094.1
	EFTUD2	ENST00000969864.1		c.2215A>T	p.Asn739Tyr	missense splice_region	Exon 21 of 28	ENSP00000639923.1
	EFTUD2	ENST00000880576.1		c.2047A>T	p.Asn683Tyr	missense splice_region	Exon 21 of 28	ENSP00000550635.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Seizure;C0557874:Global developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.65		Loss of disorder (P = 0.0289)
MVP		0.62
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.0		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: rs1057518932; hg19: chr17-42932371;