X-20132224-C-T

Position:

• chrX-20132224-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000379607.10(EIF1AX):​c.295G>A​(p.Glu99Lys) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EIF1AX ENST00000379607.10 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.52

Genes affected

EIF1AX (HGNC:3250): (eukaryotic translation initiation factor 1A X-linked) This gene encodes an essential eukaryotic translation initiation factor. The protein is required for the binding of the 43S complex (a 40S subunit, eIF2/GTP/Met-tRNAi and eIF3) to the 5' end of capped RNA. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant X-20132224-C-T is Pathogenic according to our data. Variant chrX-20132224-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800345.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF1AX	NM_001412.4	c.295G>A	p.Glu99Lys	missense_variant	5/7	ENST00000379607.10	NP_001403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF1AX	ENST00000379607.10	c.295G>A	p.Glu99Lys	missense_variant	5/7	1	NM_001412.4	ENSP00000368927	P1
EIF1AX	ENST00000379593.1	c.211G>A	p.Glu71Lys	missense_variant	4/6	3		ENSP00000368912

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Aug 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.53		Loss of ubiquitination at K104 (P = 0.0255);.;
MVP		0.95
MPC		3.3
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603415028; hg19: chrX-20150342; COSMIC: COSV63309422; COSMIC: COSV63309422;