NM_004247.4:c.1058+3_1058+7delAAGTA

Variant names:

• chr17-44868279-CTACTT-C
• rs536749831
• NM_004247.4:c.1058+3_1058+7delAAGTA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_004247.4(EFTUD2):​c.1058+3_1058+7delAAGTA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,613,102 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (33 hom.)
• Consequence: EFTUD2 NM_004247.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.75
• 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: Benign. The variant received -15 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 17-44868279-CTACTT-C is Benign according to our data. Variant chr17-44868279-CTACTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00518 (789/152234) while in subpopulation NFE AF = 0.00717 (488/68020). AF 95% confidence interval is 0.00665. There are 4 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 789 AD gene.

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.1058+3_1058+7delAAGTA		splice_region intron	N/A	NP_004238.3
	EFTUD2	NM_001258353.2		c.1058+3_1058+7delAAGTA		splice_region intron	N/A	NP_001245282.1
	EFTUD2	NM_001258354.2		c.1028+3_1028+7delAAGTA		splice_region intron	N/A	NP_001245283.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFTUD2	ENST00000426333.7	TSL:1 MANE Select	c.1058+3_1058+7delAAGTA		splice_region intron	N/A	ENSP00000392094.1
	EFTUD2	ENST00000591382.5	TSL:2	c.1058+3_1058+7delAAGTA		splice_region intron	N/A	ENSP00000467805.1
	EFTUD2	ENST00000592576.5	TSL:2	c.1028+3_1028+7delAAGTA		splice_region intron	N/A	ENSP00000465058.1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152118 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00717

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00542 AC: 1359 AN: 250748 AF XY: 0.00526

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00720

Gnomad OTH exome AF: 0.00638

GnomAD4 exome AF: 0.00655 AC: 9562 AN: 1460868 Hom.: 33 AF XY: 0.00634 AC XY: 4610 AN XY: 726734

African (AFR) AF: 0.00111 AC: 37 AN: 33450

American (AMR) AF: 0.00444 AC: 198 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00122 AC: 105 AN: 86116

European-Finnish (FIN) AF: 0.0138 AC: 737 AN: 53408

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00726 AC: 8072 AN: 1111396

Other (OTH) AF: 0.00560 AC: 338 AN: 60344

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152234 Hom.: 4 Cov.: 31 AF XY: 0.00512 AC XY: 381 AN XY: 74456

African (AFR) AF: 0.00132 AC: 55 AN: 41550

American (AMR) AF: 0.00530 AC: 81 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00717 AC: 488 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00622 Hom.: 1

Bravo AF: 0.00424

EpiCase AF: 0.00696

EpiControl AF: 0.00653

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Mandibulofacial dysostosis-microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs536749831; hg19: chr17-42945647;