rs677688

Positions:

• chr18-24440579-C-G
• chr18-24440579-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
IMPACT	NM_018439.4	c.451C>G	p.Leu151Val	missense_variant	6/11	ENST00000284202.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPACT	ENST00000284202.9	c.451C>G	p.Leu151Val	missense_variant	6/11	1	NM_018439.4	P1

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

GnomAD3 exomes AF: 0.906 AC: 226974 AN: 250564 Hom.: 103618 AF XY: 0.903 AC XY: 122301 AN XY: 135442

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 SAS exome AF: 0.873

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

Gnomad4 AFR exome AF: 0.939

Gnomad4 AMR exome AF: 0.968

Gnomad4 ASJ exome AF: 0.942

Gnomad4 EAS exome AF: 0.690

Gnomad4 SAS exome AF: 0.876

Gnomad4 FIN exome AF: 0.928

Gnomad4 NFE exome AF: 0.920

Gnomad4 OTH exome AF: 0.910

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

Gnomad4 AFR AF: 0.935

Gnomad4 AMR AF: 0.952

Gnomad4 ASJ AF: 0.937

Gnomad4 EAS AF: 0.677

Gnomad4 SAS AF: 0.868

Gnomad4 FIN AF: 0.932

Gnomad4 NFE AF: 0.923

Gnomad4 OTH AF: 0.911

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;.;.;.
MutationTaster	Benign	1.0	P
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

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