rs2250205

Positions:

• chr20-35280121-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002212.4(EIF6):​c.370-3C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001067
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
EIF6	NM_002212.4	c.370-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374450.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF6	ENST00000374450.8	c.370-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002212.4	P1

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

GnomAD3 exomes AF: 0.231 AC: 57941 AN: 250938 Hom.: 7447 AF XY: 0.237 AC XY: 32171 AN XY: 135620

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 SAS exome AF: 0.356

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

Gnomad4 AFR exome AF: 0.347

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.356

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.221

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

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.231

Alfa AF: 0.221 Hom.: 6733

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2250205; hg19: chr20-33867924; COSMIC: COSV55768447; COSMIC: COSV55768447;