chr17-7309712-G-C

Variant names:

• chr17-7309712-G-C
• rs2143008740
• NM_001970.5:c.77G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001970.5(EIF5A):​c.77G>C​(p.Arg26Pro) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF5A NM_001970.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.40
• Publications: 0 publications found

Genes affected

EIF5A (HGNC:3300): (eukaryotic translation initiation factor 5A) Enables U6 snRNA binding activity and protein N-terminus binding activity. Involved in several processes, including cellular response to virus; positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator; and tumor necrosis factor-mediated signaling pathway. Located in annulate lamellae; cytoplasm; and nucleus. Part of nuclear pore. [provided by Alliance of Genome Resources, Apr 2022]

EIF5A Gene-Disease associations (from GenCC):

• Faundes-Banka syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 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 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.407 (below the threshold of 3.09). Trascript score misZ: 4.4819 (above the threshold of 3.09). GenCC associations: The gene is linked to Faundes-Banka syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 17-7309712-G-C is Pathogenic according to our data. Variant chr17-7309712-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1064810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001970.5. 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
	EIF5A	NM_001970.5	MANE Select	c.77G>C	p.Arg26Pro	missense	Exon 2 of 6	NP_001961.1	P63241-1
	EIF5A	NM_001143760.1		c.167G>C	p.Arg56Pro	missense	Exon 2 of 6	NP_001137232.1	P63241-2
	EIF5A	NM_001143761.1		c.77G>C	p.Arg26Pro	missense	Exon 2 of 6	NP_001137233.1	P63241-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF5A	ENST00000336458.13	TSL:1 MANE Select	c.77G>C	p.Arg26Pro	missense	Exon 2 of 6	ENSP00000336776.8	P63241-1
	EIF5A	ENST00000336452.11	TSL:1	c.167G>C	p.Arg56Pro	missense	Exon 2 of 6	ENSP00000336702.7	P63241-2
	EIF5A	ENST00000416016.2	TSL:1	c.77G>C	p.Arg26Pro	missense	Exon 2 of 6	ENSP00000396073.2	P63241-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.4
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.031	D
Polyphen		0.27	B
Vest4		0.91
MutPred		0.54		Loss of MoRF binding (P = 0.0053)
MVP		0.89
MPC		2.5
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2143008740; hg19: chr17-7213031;