Variant chr18-24449824-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018439.4(IMPACT):c.765G>C(p.Leu255Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

IMPACT
NM_018439.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90

Variant links:

Genes affected

IMPACT (HGNC:20387): (impact RWD domain protein) Predicted to enable actin binding activity and ribosome binding activity. Predicted to be involved in several processes, including GCN2-mediated signaling; cellular response to starvation; and negative regulation of nitrogen compound metabolic process. Predicted to be located in cytoplasm. Predicted to be part of polysome. [provided by Alliance of Genome Resources, Apr 2022]

IMPACT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IMPACT	NM_018439.4 linkuse as main transcript	c.765G>C	p.Leu255Phe	missense_variant	10/11	ENST00000284202.9	NP_060909.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IMPACT	ENST00000284202.9 linkuse as main transcript	c.765G>C	p.Leu255Phe	missense_variant	10/11	1	NM_018439.4	ENSP00000284202	P1	Q9P2X3-1
IMPACT	ENST00000580706.1 linkuse as main transcript	n.2001G>C		non_coding_transcript_exon_variant	9/10	1
IMPACT	ENST00000648078.1 linkuse as main transcript	c.765G>C	p.Leu255Phe	missense_variant	10/12			ENSP00000497783
IMPACT	ENST00000581278.1 linkuse as main transcript	c.51G>C	p.Leu17Phe	missense_variant	2/4	2		ENSP00000463895

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251200

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459550

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.765G>C (p.L255F) alteration is located in exon 10 (coding exon 10) of the IMPACT gene. This alteration results from a G to C substitution at nucleotide position 765, causing the leucine (L) at amino acid position 255 to be replaced by a phenylalanine (F). 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

0.71

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Benign

0.17

T;.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.9

D;.;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

D;.;.

Sift4G

Uncertain

0.018

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.78

MutPred

0.47

Gain of ubiquitination at K258 (P = 0.1434);Gain of ubiquitination at K258 (P = 0.1434);.;

MVP

0.54

MPC

0.40

ClinPred

0.71

GERP RS

4.6

Varity_R

0.39

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over