chr15-40020940-C-T

Variant names:

• chr15-40020940-C-T
• rs3207297
• NM_001013703.4:c.4215C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001013703.4(EIF2AK4):​c.4215C>T​(p.Gly1405Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,611,428 control chromosomes in the GnomAD database, including 101,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9232 hom., cov: 31)
  • Exomes 𝑓: 0.35 (91888 hom.)
• Consequence: EIF2AK4 NM_001013703.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0170
• Publications: 13 publications found

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]

EIF2AK4 Gene-Disease associations (from GenCC):

• pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary venoocclusive disease 2

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary venoocclusive disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306490 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 15-40020940-C-T is Benign according to our data. Variant chr15-40020940-C-T is described in ClinVar as Benign. ClinVar VariationId is 381184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.017 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013703.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	NM_001013703.4	MANE Select	c.4215C>T	p.Gly1405Gly	synonymous	Exon 31 of 39	NP_001013725.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.4215C>T	p.Gly1405Gly	synonymous	Exon 31 of 39	ENSP00000263791.5
	EIF2AK4	ENST00000558629.5	TSL:1	n.3132C>T		non_coding_transcript_exon	Exon 14 of 22
	EIF2AK4	ENST00000560855.5	TSL:5	c.3546C>T	p.Gly1182Gly	synonymous	Exon 26 of 34	ENSP00000453575.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52926 AN: 151696 Hom.: 9225 Cov.: 31

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.341 AC: 84664 AN: 248142 AF XY: 0.346

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.244

Gnomad FIN exome AF: 0.330

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.353 AC: 515927 AN: 1459612 Hom.: 91888 Cov.: 36 AF XY: 0.355 AC XY: 257867 AN XY: 726128

African (AFR) AF: 0.337 AC: 11276 AN: 33414

American (AMR) AF: 0.290 AC: 12899 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9795 AN: 26086

East Asian (EAS) AF: 0.285 AC: 11279 AN: 39638

South Asian (SAS) AF: 0.380 AC: 32628 AN: 85880

European-Finnish (FIN) AF: 0.331 AC: 17652 AN: 53368

Middle Eastern (MID) AF: 0.414 AC: 2345 AN: 5666

European-Non Finnish (NFE) AF: 0.357 AC: 396457 AN: 1110740

Other (OTH) AF: 0.358 AC: 21596 AN: 60290

GnomAD4 genome AF: 0.349 AC: 52951 AN: 151816 Hom.: 9232 Cov.: 31 AF XY: 0.347 AC XY: 25758 AN XY: 74194

African (AFR) AF: 0.340 AC: 14055 AN: 41360

American (AMR) AF: 0.328 AC: 4997 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1268 AN: 3466

East Asian (EAS) AF: 0.254 AC: 1306 AN: 5138

South Asian (SAS) AF: 0.362 AC: 1744 AN: 4812

European-Finnish (FIN) AF: 0.331 AC: 3491 AN: 10548

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24758 AN: 67930

Other (OTH) AF: 0.376 AC: 792 AN: 2104

Alfa AF: 0.361 Hom.: 45293

Bravo AF: 0.348

Asia WGS AF: 0.294 AC: 1025 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.375

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial pulmonary capillary hemangiomatosis (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.8
DANN	Benign	0.69
PhyloP100		-0.017
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3207297; hg19: chr15-40313141; COSMIC: COSV55468419; COSMIC: COSV55468419;