chrX-20132224-C-T

Variant names:

• chrX-20132224-C-T
• rs1603415028
• NM_001412.4:c.295G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001412.4(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 NM_001412.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.52
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.3908 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09).
• 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 VariationId is 800345.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001412.4. 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
	EIF1AX	NM_001412.4	MANE Select	c.295G>A	p.Glu99Lys	missense	Exon 5 of 7	NP_001403.1	P47813

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF1AX	ENST00000379607.10	TSL:1 MANE Select	c.295G>A	p.Glu99Lys	missense	Exon 5 of 7	ENSP00000368927.5	P47813
	EIF1AX	ENST00000914219.1		c.289G>A	p.Glu97Lys	missense	Exon 5 of 7	ENSP00000584278.1
	EIF1AX	ENST00000914220.1		c.286G>A	p.Glu96Lys	missense	Exon 5 of 7	ENSP00000584279.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple myeloma (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	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
Mutation Taster		=42/58	disease causing (ClinVar)

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

Other links and lift over

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