rs2250205

Variant names:

• chr20-35280121-G-A
• rs2250205
• NM_002212.4:c.370-3C>T

Variant summary

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

The NM_002212.4(EIF6):​c.370-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,613,118 control chromosomes in the GnomAD database, including 42,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5038 hom., cov: 31)
  • Exomes 𝑓: 0.22 (37324 hom.)
• Consequence: EIF6 NM_002212.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001067
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945
• Publications: 34 publications found

Genes affected

EIF6 (HGNC:6159): (eukaryotic translation initiation factor 6) Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functional component of hemidesmosomes is the integrin beta-4 subunit (ITGB4), a protein containing two fibronectin type III domains. The protein encoded by this gene binds to the fibronectin type III domains of ITGB4 and may help link ITGB4 to the intermediate filament cytoskeleton. The encoded protein, which is insoluble and found both in the nucleus and in the cytoplasm, can function as a translation initiation factor and prevent the association of the 40S and 60S ribosomal subunits. Multiple non-protein coding transcript variants and variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

EIF6 Gene-Disease associations (from GenCC):

• Shwachman-Diamond syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox

ENSG00000261582 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF6	NM_002212.4	c.370-3C>T		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000374450.8	NP_002203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF6	ENST00000374450.8	c.370-3C>T		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_002212.4	ENSP00000363574.3
ENSG00000261582	ENST00000444717.1	n.-78C>T		upstream_gene_variant		3		ENSP00000489186.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37767 AN: 151966 Hom.: 5021 Cov.: 31

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.231 AC: 57941 AN: 250938 AF XY: 0.237

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.220 AC: 321567 AN: 1461032 Hom.: 37324 Cov.: 36 AF XY: 0.224 AC XY: 162845 AN XY: 726838

African (AFR) AF: 0.347 AC: 11627 AN: 33464

American (AMR) AF: 0.119 AC: 5312 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5834 AN: 26098

East Asian (EAS) AF: 0.194 AC: 7713 AN: 39694

South Asian (SAS) AF: 0.356 AC: 30737 AN: 86222

European-Finnish (FIN) AF: 0.224 AC: 11966 AN: 53392

Middle Eastern (MID) AF: 0.211 AC: 1217 AN: 5760

European-Non Finnish (NFE) AF: 0.210 AC: 233789 AN: 1111340

Other (OTH) AF: 0.221 AC: 13372 AN: 60372

GnomAD4 genome AF: 0.249 AC: 37823 AN: 152086 Hom.: 5038 Cov.: 31 AF XY: 0.249 AC XY: 18507 AN XY: 74340

African (AFR) AF: 0.340 AC: 14101 AN: 41476

American (AMR) AF: 0.170 AC: 2604 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 772 AN: 3472

East Asian (EAS) AF: 0.212 AC: 1096 AN: 5172

South Asian (SAS) AF: 0.345 AC: 1665 AN: 4822

European-Finnish (FIN) AF: 0.227 AC: 2398 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14431 AN: 67966

Other (OTH) AF: 0.231 AC: 487 AN: 2108

Alfa AF: 0.225 Hom.: 13638

Bravo AF: 0.245

Asia WGS AF: 0.316 AC: 1098 AN: 3478

EpiCase AF: 0.211

EpiControl AF: 0.216

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.050		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: rs2250205; hg19: chr20-33867924; COSMIC: COSV55768447; COSMIC: COSV55768447;