22-31440755-G-A

Variant names:

• chr22-31440755-G-A
• NM_019843.4:c.2665C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019843.4(EIF4ENIF1):​c.2665C>T​(p.Pro889Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4ENIF1 NM_019843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.786
• Publications: 0 publications found

Genes affected

EIF4ENIF1 (HGNC:16687): (eukaryotic translation initiation factor 4E nuclear import factor 1) The protein encoded by this gene is a nucleocytoplasmic shuttle protein for the translation initiation factor eIF4E. This shuttle protein interacts with the importin alpha-beta complex to mediate nuclear import of eIF4E. It is predominantly cytoplasmic; its own nuclear import is regulated by a nuclear localization signal and nuclear export signals. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

DRG1 (HGNC:3029): (developmentally regulated GTP binding protein 1) Enables several functions, including GTPase activity; identical protein binding activity; and potassium ion binding activity. Involved in positive regulation of microtubule polymerization and regulation of mitotic spindle assembly. Located in cytosol and nuclear body. Part of polysome. [provided by Alliance of Genome Resources, Apr 2022]

DRG1 Gene-Disease associations (from GenCC):

• Tan-Almurshedi syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07989338).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019843.4. 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
	EIF4ENIF1	NM_019843.4	MANE Select	c.2665C>T	p.Pro889Ser	missense	Exon 18 of 19	NP_062817.2	Q9NRA8-1
	EIF4ENIF1	NM_001164501.2		c.2665C>T	p.Pro889Ser	missense	Exon 18 of 19	NP_001157973.1	Q9NRA8-1
	EIF4ENIF1	NM_001164502.2		c.2143C>T	p.Pro715Ser	missense	Exon 16 of 17	NP_001157974.1	Q9NRA8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4ENIF1	ENST00000330125.10	TSL:1 MANE Select	c.2665C>T	p.Pro889Ser	missense	Exon 18 of 19	ENSP00000328103.5	Q9NRA8-1
	EIF4ENIF1	ENST00000397525.5	TSL:1	c.2665C>T	p.Pro889Ser	missense	Exon 18 of 19	ENSP00000380659.1	Q9NRA8-1
	EIF4ENIF1	ENST00000344710.9	TSL:1	c.2143C>T	p.Pro715Ser	missense	Exon 16 of 17	ENSP00000342927.5	Q9NRA8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.035	N
PhyloP100		0.79
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.044
Sift	Benign	0.19	T
Sift4G	Benign	0.52	T
Polyphen		0.012	B
Vest4		0.24
MutPred		0.28		Gain of glycosylation at P889 (P = 0.0708)
MVP		0.12
MPC		0.14
ClinPred		0.17	T
GERP RS		3.6
Varity_R		0.045
gMVP		0.20
Mutation Taster		=93/7	polymorphism

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

hg19: chr22-31836741;