NM_018439.4:c.244C>T

Variant names:

• chr18-24430347-C-T
• rs759107422
• NM_018439.4:c.244C>T

Variant summary

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

The NM_018439.4(IMPACT):​c.244C>T​(p.Arg82Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,596,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IMPACT NM_018439.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• Publications: 0 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: 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_018439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPACT	NM_018439.4	MANE Select	c.244C>T	p.Arg82Cys	missense	Exon 4 of 11	NP_060909.2	Q9P2X3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPACT	ENST00000284202.9	TSL:1 MANE Select	c.244C>T	p.Arg82Cys	missense	Exon 4 of 11	ENSP00000284202.4	Q9P2X3-1
	IMPACT	ENST00000580706.1	TSL:1	n.1480C>T		non_coding_transcript_exon	Exon 3 of 10
	IMPACT	ENST00000648078.1		c.244C>T	p.Arg82Cys	missense	Exon 4 of 12	ENSP00000497783.1	A0A3B3ITH3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000839 AC: 2 AN: 238474 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444762 Hom.: 0 Cov.: 28 AF XY: 0.00000278 AC XY: 2 AN XY: 718988

African (AFR) AF: 0.00 AC: 0 AN: 32748

American (AMR) AF: 0.00 AC: 0 AN: 40344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25700

East Asian (EAS) AF: 0.00 AC: 0 AN: 39122

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82602

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106070

Other (OTH) AF: 0.0000168 AC: 1 AN: 59556

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74262

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.17
Sift	Benign	0.047	D
Sift4G	Benign	0.11	T
Polyphen		0.030	B
Vest4		0.70
MutPred		0.62		Loss of disorder (P = 0.0075)
MVP		0.42
MPC		0.090
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.58
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs759107422; hg19: chr18-22010311;