chr18-24440579-C-G

Variant names:

• chr18-24440579-C-G
• rs677688
• NM_018439.4:c.451C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018439.4(IMPACT):​c.451C>G​(p.Leu151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 1,612,828 control chromosomes in the GnomAD database, including 675,851 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.92 (64597 hom., cov: 33)
  • Exomes 𝑓: 0.91 (611254 hom.)
• Consequence: IMPACT NM_018439.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.698
• Publications: 32 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.073872E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IMPACT	NM_018439.4	c.451C>G	p.Leu151Val	missense_variant	Exon 6 of 11	ENST00000284202.9	NP_060909.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IMPACT	ENST00000284202.9	c.451C>G	p.Leu151Val	missense_variant	Exon 6 of 11	1	NM_018439.4	ENSP00000284202.4

Frequencies

GnomAD3 genomes AF: 0.920 AC: 139934 AN: 152164 Hom.: 64539 Cov.: 33

Gnomad AFR AF: 0.935

Gnomad AMI AF: 0.918

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.915

GnomAD2 exomes AF: 0.906 AC: 226974 AN: 250564 AF XY: 0.903

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.970

Gnomad ASJ exome AF: 0.941

Gnomad EAS exome AF: 0.662

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.923

Gnomad OTH exome AF: 0.915

GnomAD4 exome AF: 0.914 AC: 1334535 AN: 1460546 Hom.: 611254 Cov.: 40 AF XY: 0.913 AC XY: 663143 AN XY: 726622

African (AFR) AF: 0.939 AC: 31377 AN: 33428

American (AMR) AF: 0.968 AC: 43137 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 24613 AN: 26124

East Asian (EAS) AF: 0.690 AC: 27349 AN: 39640

South Asian (SAS) AF: 0.876 AC: 75383 AN: 86038

European-Finnish (FIN) AF: 0.928 AC: 49592 AN: 53414

Middle Eastern (MID) AF: 0.945 AC: 5447 AN: 5762

European-Non Finnish (NFE) AF: 0.920 AC: 1022748 AN: 1111258

Other (OTH) AF: 0.910 AC: 54889 AN: 60336

GnomAD4 genome AF: 0.920 AC: 140053 AN: 152282 Hom.: 64597 Cov.: 33 AF XY: 0.918 AC XY: 68374 AN XY: 74454

African (AFR) AF: 0.935 AC: 38831 AN: 41534

American (AMR) AF: 0.952 AC: 14573 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3252 AN: 3470

East Asian (EAS) AF: 0.677 AC: 3499 AN: 5170

South Asian (SAS) AF: 0.868 AC: 4194 AN: 4830

European-Finnish (FIN) AF: 0.932 AC: 9890 AN: 10614

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.923 AC: 62788 AN: 68042

Other (OTH) AF: 0.911 AC: 1924 AN: 2112

Alfa AF: 0.918 Hom.: 48412

Bravo AF: 0.922

TwinsUK AF: 0.913 AC: 3387

ALSPAC AF: 0.915 AC: 3528

ESP6500AA AF: 0.935 AC: 4120

ESP6500EA AF: 0.922 AC: 7929

ExAC AF: 0.903 AC: 109679

Asia WGS AF: 0.772 AC: 2684 AN: 3478

EpiCase AF: 0.929

EpiControl AF: 0.925

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.8
DANN	Benign	0.48
DEOGEN2	Benign	0.012	T;.;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00067	N
LIST_S2	Benign	0.046	T;T;T;T
MetaRNN	Benign	0.0000011	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.;.;.
PhyloP100		0.70
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.27	N;.;.;.
REVEL	Benign	0.017
Sift	Benign	0.78	T;.;.;.
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.016
MPC		0.063
ClinPred		0.00027	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs677688; hg19: chr18-22020543; COSMIC: COSV52421531; COSMIC: COSV52421531;