Genetic Variant NM_001013703.4:c.2631+672T>C (chr15-39991049-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001013703.4(EIF2AK4):c.2631+672T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 152,444 control chromosomes in the GnomAD database, including 22,900 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.53 ( 22819 hom., cov: 33)

Exomes 𝑓: 0.65 ( 81 hom. )

Consequence

EIF2AK4
NM_001013703.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.401

Publications

5 publications found

Variant links:

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

EIF2AK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.639 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.2631+672T>C		intron	N/A	NP_001013725.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.2631+672T>C	intron	N/A	ENSP00000263791.5
EIF2AK4	ENST00000560855.5	TSL:5	c.1962+672T>C	intron	N/A	ENSP00000453575.1
EIF2AK4	ENST00000558629.5	TSL:1	n.-117T>C	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.530

AC:

80517

AN:

151956

Hom.:

22815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.325

Gnomad AMI

AF:

0.646

Gnomad AMR

AF:

0.496

Gnomad ASJ

AF:

0.685

Gnomad EAS

AF:

0.520

Gnomad SAS

AF:

0.496

Gnomad FIN

AF:

0.596

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.568

GnomAD4 exome

AF:

0.649

AC:

240

AN:

370

Hom.:

AF XY:

0.643

AC XY:

148

AN XY:

230

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.750

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

0.617

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.675

AC:

158

AN:

234

Other (OTH)

AF:

0.556

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.530

AC:

80560

AN:

152074

Hom.:

22819

Cov.:

AF XY:

0.529

AC XY:

39314

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.326

AC:

13504

AN:

41464

American (AMR)

AF:

0.496

AC:

7582

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

2378

AN:

3472

East Asian (EAS)

AF:

0.519

AC:

2678

AN:

5158

South Asian (SAS)

AF:

0.497

AC:

2398

AN:

4824

European-Finnish (FIN)

AF:

0.596

AC:

6305

AN:

10578

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.644

AC:

43769

AN:

67970

Other (OTH)

AF:

0.562

AC:

1188

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1871

3742

5614

7485

9356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.609

Hom.:

50110

Bravo

AF:

0.517

Asia WGS

AF:

0.473

AC:

1643

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

2.8

(source)

DANN

Benign

0.67

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over