20-35284388-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_002212.4(EIF6):c.100T>C(p.Phe34Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: EIF6 NM_002212.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.40

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF6	NM_002212.4	c.100T>C	p.Phe34Leu	missense_variant	2/7	ENST00000374450.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF6	ENST00000374450.8	c.100T>C	p.Phe34Leu	missense_variant	2/7	1	NM_002212.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000213 AC: 53 AN: 248356 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134904

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000285 AC: 417 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.000289 AC XY: 210 AN XY: 727132

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000939

Gnomad4 NFE exome AF: 0.000348

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000363

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.100T>C (p.F34L) alteration is located in exon 1 (coding exon 1) of the EIF6 gene. This alteration results from a T to C substitution at nucleotide position 100, causing the phenylalanine (F) at amino acid position 34 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	3.3	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;.
Polyphen		0.057	B;.;B;.
Vest4		0.80
MutPred		0.60		Gain of disorder (P = 0.2756);Gain of disorder (P = 0.2756);Gain of disorder (P = 0.2756);Gain of disorder (P = 0.2756);
MVP		0.65
MPC		0.44
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs144868364; hg19: chr20-33872191;