1-153642397-G-A

Variant names:

• chr1-153642397-G-A
• rs942120799
• NM_015607.4:c.371G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015607.4(CHTOP):​c.371G>A​(p.Arg124Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHTOP NM_015607.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.70
• Publications: 0 publications found

Genes affected

CHTOP (HGNC:24511): (chromatin target of PRMT1) This gene encodes a small nuclear protein that is characterized by an arginine and glycine rich region. This protein may have an important role in the regulation of fetal globin gene expression and in the activation of estrogen-responsive genes. A recent study reported that this protein binds 5-hydroxymethylcytosine (5hmC) and associates with an arginine methyltransferase complex (methylosome), which promotes methylation of arginine 3 of histone H4 (H4R3) and activation of genes involved in glioblastomagenesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29558405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015607.4. 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
	CHTOP	NM_015607.4	MANE Select	c.371G>A	p.Arg124Lys	missense	Exon 4 of 6	NP_056422.2
	CHTOP	NM_001206612.2		c.374G>A	p.Arg125Lys	missense	Exon 4 of 6	NP_001193541.1	Q9Y3Y2-3
	CHTOP	NM_001317077.2		c.371G>A	p.Arg124Lys	missense	Exon 4 of 5	NP_001304006.1	Q9Y3Y2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHTOP	ENST00000368694.8	TSL:1 MANE Select	c.371G>A	p.Arg124Lys	missense	Exon 4 of 6	ENSP00000357683.3	Q9Y3Y2-1
	CHTOP	ENST00000368690.7	TSL:1	c.374G>A	p.Arg125Lys	missense	Exon 4 of 6	ENSP00000357679.4	Q9Y3Y2-3
	CHTOP	ENST00000368687.1	TSL:1	c.296G>A	p.Arg99Lys	missense	Exon 2 of 4	ENSP00000357676.1	X6R700

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.072	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		8.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.51
Sift	Benign	0.33	T
Sift4G	Benign	0.66	T
Polyphen		0.51	P
Vest4		0.45
MutPred		0.30		Loss of methylation at R124 (P = 0.012)
MVP		0.73
MPC		0.64
ClinPred		0.57	D
GERP RS		5.6
Varity_R		0.33
gMVP		0.32
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs942120799; hg19: chr1-153614873;