Genetic Variant NM_018463.4:c.437G>C (chr12-2820116-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018463.4(ITFG2):c.437G>C(p.Gly146Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,232 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITFG2
NM_018463.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.73

Publications

0 publications found

Variant links:

Genes affected

ITFG2 (HGNC:30879): (integrin alpha FG-GAP repeat containing 2) Involved in cellular response to amino acid starvation; cellular response to glucose starvation; and negative regulation of TORC1 signaling. Located in lysosomal membrane. Part of KICSTOR complex. [provided by Alliance of Genome Resources, Apr 2022]

ITFG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018463.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITFG2	NM_018463.4	MANE Select	c.437G>C	p.Gly146Ala	missense	Exon 5 of 12	NP_060933.3
ITFG2	NR_130744.3		n.606G>C		non_coding_transcript_exon	Exon 5 of 14
ITFG2	NR_147202.2		n.508G>C		non_coding_transcript_exon	Exon 5 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITFG2	ENST00000228799.7	TSL:1 MANE Select	c.437G>C	p.Gly146Ala	missense	Exon 5 of 12	ENSP00000228799.2	Q969R8-1
ITFG2	ENST00000537851.5	TSL:1	n.127G>C		non_coding_transcript_exon	Exon 2 of 9	ENSP00000445769.1	F5H1D0
ITFG2	ENST00000917242.1		c.437G>C	p.Gly146Ala	missense	Exon 5 of 12	ENSP00000587301.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461232

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726962

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111684

Other (OTH)

AF:

0.0000166

AC:

AN:

60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Benign

0.31

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.2

PhyloP100

9.7

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.47

Sift

Benign

0.088

Sift4G

Benign

0.17

Polyphen

1.0

Vest4

0.91

MutPred

0.59

Gain of catalytic residue at E142 (P = 0.002)

MVP

0.92

MPC

0.94

ClinPred

0.98

GERP RS

4.6

Varity_R

0.49

gMVP

0.77

Mutation Taster

=198/102

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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