NM_004247.4:c.762T>C

Variant names:

• chr17-44876041-A-G
• rs2289674
• NM_004247.4:c.762T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004247.4(EFTUD2):​c.762T>C​(p.Thr254Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,850 control chromosomes in the GnomAD database, including 33,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T254T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3367 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30431 hom.)
• Consequence: EFTUD2 NM_004247.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.354
• Publications: 32 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-44876041-A-G is Benign according to our data. Variant chr17-44876041-A-G is described in ClinVar as Benign. ClinVar VariationId is 128973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

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.762T>C	p.Thr254Thr	synonymous	Exon 10 of 28	NP_004238.3
	EFTUD2	NM_001258353.2		c.762T>C	p.Thr254Thr	synonymous	Exon 10 of 28	NP_001245282.1
	EFTUD2	NM_001258354.2		c.732T>C	p.Thr244Thr	synonymous	Exon 10 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.762T>C	p.Thr254Thr	synonymous	Exon 10 of 28	ENSP00000392094.1
	EFTUD2	ENST00000969864.1		c.762T>C	p.Thr254Thr	synonymous	Exon 10 of 28	ENSP00000639923.1
	EFTUD2	ENST00000880576.1		c.762T>C	p.Thr254Thr	synonymous	Exon 10 of 28	ENSP00000550635.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30547 AN: 151982 Hom.: 3356 Cov.: 31

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.170 AC: 42782 AN: 251356 AF XY: 0.169

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.200 AC: 292605 AN: 1461750 Hom.: 30431 Cov.: 33 AF XY: 0.197 AC XY: 142917 AN XY: 727172

African (AFR) AF: 0.259 AC: 8663 AN: 33478

American (AMR) AF: 0.108 AC: 4820 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4586 AN: 26134

East Asian (EAS) AF: 0.149 AC: 5907 AN: 39698

South Asian (SAS) AF: 0.115 AC: 9884 AN: 86242

European-Finnish (FIN) AF: 0.161 AC: 8614 AN: 53412

Middle Eastern (MID) AF: 0.0941 AC: 538 AN: 5716

European-Non Finnish (NFE) AF: 0.214 AC: 238400 AN: 1111954

Other (OTH) AF: 0.185 AC: 11193 AN: 60392

GnomAD4 genome AF: 0.201 AC: 30580 AN: 152100 Hom.: 3367 Cov.: 31 AF XY: 0.195 AC XY: 14515 AN XY: 74380

African (AFR) AF: 0.263 AC: 10905 AN: 41462

American (AMR) AF: 0.116 AC: 1772 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3468

East Asian (EAS) AF: 0.144 AC: 748 AN: 5186

South Asian (SAS) AF: 0.106 AC: 512 AN: 4818

European-Finnish (FIN) AF: 0.154 AC: 1635 AN: 10588

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13733 AN: 67974

Other (OTH) AF: 0.156 AC: 329 AN: 2110

Alfa AF: 0.201 Hom.: 3016

Bravo AF: 0.204

Asia WGS AF: 0.131 AC: 459 AN: 3478

EpiCase AF: 0.195

EpiControl AF: 0.189

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Mandibulofacial dysostosis-microcephaly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.2
DANN	Benign	0.61
PhyloP100		-0.35
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2289674; hg19: chr17-42953409; COSMIC: COSV68183230; COSMIC: COSV68183230;