1-230868218-C-A

Variant names:

• chr1-230868218-C-A
• rs774489801
• NM_032800.3:c.295G>T

Variant summary

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

The NM_032800.3(C1orf198):​c.295G>T​(p.Gly99Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,400 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. G99R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: C1orf198 NM_032800.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• Publications: 0 publications found

Genes affected

C1orf198 (HGNC:25900): (chromosome 1 open reading frame 198) Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000223393 (HGNC:):

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=0.37470752).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032800.3. 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
	C1orf198	NM_032800.3	MANE Select	c.295G>T	p.Gly99Trp	missense	Exon 1 of 4	NP_116189.1	Q9H425-1
	C1orf198	NM_001136494.2		c.181G>T	p.Gly61Trp	missense	Exon 3 of 6	NP_001129966.1	Q9H425-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf198	ENST00000366663.10	TSL:1 MANE Select	c.295G>T	p.Gly99Trp	missense	Exon 1 of 4	ENSP00000355623.5	Q9H425-1
	C1orf198	ENST00000470540.5	TSL:2	c.181G>T	p.Gly61Trp	missense	Exon 3 of 6	ENSP00000428172.1	Q9H425-3
	C1orf198	ENST00000522201.1	TSL:3	c.166G>T	p.Gly56Trp	missense	Exon 2 of 4	ENSP00000429503.1	E5RI90

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385400 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684792

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

African (AFR) AF: 0.00 AC: 0 AN: 28638

American (AMR) AF: 0.00 AC: 0 AN: 35282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24374

East Asian (EAS) AF: 0.00 AC: 0 AN: 33346

South Asian (SAS) AF: 0.00 AC: 0 AN: 78836

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076540

Other (OTH) AF: 0.00 AC: 0 AN: 57488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PROVEAN	Benign	0.0	N
REVEL	Benign	0.13
Sift	Benign	0.18	T
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.32		Loss of disorder (P = 0.009)
MVP		0.30
MPC		2.2
ClinPred		0.74	D
GERP RS		3.5
PromoterAI		-0.092	Neutral
Varity_R		0.082
gMVP		0.57
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774489801; hg19: chr1-231003964;