15-39934184-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001013703.4(EIF2AK4):c.-12C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,514,278 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (12 hom.)
• Consequence: EIF2AK4 NM_001013703.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.236

Genes affected

EIF2AK4 (HGNC:19687): (eukaryotic translation initiation factor 2 alpha kinase 4) This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-39934184-C-A is Benign according to our data. Variant chr15-39934184-C-A is described in ClinVar as [Benign]. Clinvar id is 993783.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00905 (1376/152126) while in subpopulation AFR AF= 0.031 (1286/41540). AF 95% confidence interval is 0.0296. There are 25 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.-12C>A		5_prime_UTR_variant	1/39	ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.-12C>A		5_prime_UTR_variant	1/39	2	NM_001013703.4	P1
EIF2AK4	ENST00000559624.5	c.-12C>A		5_prime_UTR_variant	1/11	1
EIF2AK4	ENST00000560648.1	c.-12C>A		5_prime_UTR_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1368 AN: 152014 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00174 AC: 206 AN: 118704 Hom.: 1 AF XY: 0.00139 AC XY: 92 AN XY: 66178

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000960

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000801 AC: 1091 AN: 1362152 Hom.: 12 Cov.: 29 AF XY: 0.000696 AC XY: 468 AN XY: 672638

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000651

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000507

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00905 AC: 1376 AN: 152126 Hom.: 25 Cov.: 33 AF XY: 0.00836 AC XY: 622 AN XY: 74386

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00424 Hom.: 0

Bravo AF: 0.00977

Asia WGS AF: 0.00202 AC: 8 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial pulmonary capillary hemangiomatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	8.7
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs114097242; hg19: chr15-40226385;