Genetic Variant EIF6:p.Met62Ile (chr20-35284183-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002212.4(EIF6):c.186G>A(p.Met62Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M62K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EIF6
NM_002212.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Publications

0 publications found

Variant links:

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 links:

FAM83C-AS1 (HGNC:16113): (FAM83C antisense RNA 1)

FAM83C-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002212.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF6	NM_002212.4	MANE Select	c.186G>A	p.Met62Ile	missense	Exon 3 of 7	NP_002203.1	P56537-1
EIF6	NM_001267810.1		c.186G>A	p.Met62Ile	missense	Exon 3 of 7	NP_001254739.1	P56537-1
EIF6	NM_181468.2		c.186G>A	p.Met62Ile	missense	Exon 2 of 6	NP_852133.1	P56537-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF6	ENST00000374450.8	TSL:1 MANE Select	c.186G>A	p.Met62Ile	missense	Exon 3 of 7	ENSP00000363574.3	P56537-1
EIF6	ENST00000374436.7	TSL:1	c.186G>A	p.Met62Ile	missense	Exon 2 of 6	ENSP00000363559.3	P56537-1
EIF6	ENST00000447927.6	TSL:1	n.186G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000411450.2	A0A0B4J1Y7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441942

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714808

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.00

AC:

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25640

East Asian (EAS)

AF:

0.00

AC:

AN:

39392

South Asian (SAS)

AF:

0.00

AC:

AN:

85536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101884

Other (OTH)

AF:

0.00

AC:

AN:

59696

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.45

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.43

PhyloP100

4.5

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Vest4

0.58

MutPred

0.73

Gain of sheet (P = 0.0827)

MVP

0.55

ClinPred

0.89

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over