NM_014413.4:c.1531-651A>G

Variant names:

• chr7-6027612-T-C
• rs10487933
• NM_014413.4:c.1531-651A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014413.4(EIF2AK1):​c.1531-651A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 151,864 control chromosomes in the GnomAD database, including 7,422 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 0.29 (7422 hom., cov: 31)
• Consequence: EIF2AK1 NM_014413.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216
• Publications: 7 publications found

Genes affected

EIF2AK1 (HGNC:24921): (eukaryotic translation initiation factor 2 alpha kinase 1) The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

EIF2AK1 Gene-Disease associations (from GenCC):

• leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK1	NM_014413.4	c.1531-651A>G		intron_variant	Intron 13 of 14	ENST00000199389.11	NP_055228.2
EIF2AK1	NM_001134335.2	c.1528-651A>G		intron_variant	Intron 13 of 14		NP_001127807.1
EIF2AK1	XM_047420200.1	c.907-651A>G		intron_variant	Intron 9 of 10		XP_047276156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK1	ENST00000199389.11	c.1531-651A>G		intron_variant	Intron 13 of 14	1	NM_014413.4	ENSP00000199389.6
EIF2AK1	ENST00000490523.1	n.226-651A>G		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44000 AN: 151746 Hom.: 7408 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.290 AC: 44041 AN: 151864 Hom.: 7422 Cov.: 31 AF XY: 0.292 AC XY: 21693 AN XY: 74234

African (AFR) AF: 0.448 AC: 18552 AN: 41396

American (AMR) AF: 0.255 AC: 3880 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3460

East Asian (EAS) AF: 0.493 AC: 2531 AN: 5132

South Asian (SAS) AF: 0.289 AC: 1390 AN: 4808

European-Finnish (FIN) AF: 0.239 AC: 2514 AN: 10540

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13810 AN: 67970

Other (OTH) AF: 0.265 AC: 559 AN: 2110

Alfa AF: 0.172 Hom.: 501

Bravo AF: 0.296

Asia WGS AF: 0.399 AC: 1386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.2
DANN	Benign	0.77
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10487933; hg19: chr7-6067243;