15-40016658-G-T

Variant names:

• chr15-40016658-G-T
• rs35602605
• NM_001013703.4:c.3916G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001013703.4(EIF2AK4):​c.3916G>T​(p.Gly1306Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,804 control chromosomes in the GnomAD database, including 22,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1470 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20961 hom.)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.90
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002770543).
• BP6: Variant 15-40016658-G-T is Benign according to our data. Variant chr15-40016658-G-T is described in ClinVar as Benign. ClinVar VariationId is 381182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 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.3916G>T	p.Gly1306Cys	missense	Exon 28 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.3916G>T	p.Gly1306Cys	missense	Exon 28 of 39	ENSP00000263791.5
	EIF2AK4	ENST00000558629.5	TSL:1	n.2833G>T		non_coding_transcript_exon	Exon 11 of 22
	EIF2AK4	ENST00000560855.5	TSL:5	c.3247G>T	p.Gly1083Cys	missense	Exon 23 of 34	ENSP00000453575.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18989 AN: 152078 Hom.: 1471 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.129 AC: 32266 AN: 249278 AF XY: 0.132

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.0793

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.00284

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.163 AC: 238386 AN: 1461608 Hom.: 20961 Cov.: 32 AF XY: 0.161 AC XY: 117323 AN XY: 727114

African (AFR) AF: 0.0424 AC: 1420 AN: 33456

American (AMR) AF: 0.0824 AC: 3683 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4394 AN: 26132

East Asian (EAS) AF: 0.00249 AC: 99 AN: 39696

South Asian (SAS) AF: 0.0831 AC: 7160 AN: 86198

European-Finnish (FIN) AF: 0.162 AC: 8668 AN: 53400

Middle Eastern (MID) AF: 0.130 AC: 750 AN: 5766

European-Non Finnish (NFE) AF: 0.183 AC: 203465 AN: 1111878

Other (OTH) AF: 0.145 AC: 8747 AN: 60382

GnomAD4 genome AF: 0.125 AC: 18990 AN: 152196 Hom.: 1470 Cov.: 32 AF XY: 0.122 AC XY: 9105 AN XY: 74398

African (AFR) AF: 0.0470 AC: 1952 AN: 41532

American (AMR) AF: 0.108 AC: 1652 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3472

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5194

South Asian (SAS) AF: 0.0797 AC: 384 AN: 4816

European-Finnish (FIN) AF: 0.161 AC: 1702 AN: 10568

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12212 AN: 68004

Other (OTH) AF: 0.129 AC: 272 AN: 2114

Alfa AF: 0.153 Hom.: 6749

Bravo AF: 0.118

TwinsUK AF: 0.193 AC: 715

ALSPAC AF: 0.188 AC: 723

ESP6500AA AF: 0.0504 AC: 191

ESP6500EA AF: 0.178 AC: 1463

ExAC AF: 0.131 AC: 15765

Asia WGS AF: 0.0510 AC: 177 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.170

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Oct 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial pulmonary capillary hemangiomatosis Benign:1

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.32
MPC		1.0
ClinPred		0.031	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.81
Mutation Taster		=41/59	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: rs35602605; hg19: chr15-40308859; COSMIC: COSV55474716; COSMIC: COSV55474716;