chr20-45941159-A-G

Position:

• chr20-45941159-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022104.4(PCIF1):​c.625A>G​(p.Ile209Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCIF1 NM_022104.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

PCIF1 (HGNC:16200): (phosphorylated CTD interacting factor 1) Enables RNA polymerase II C-terminal domain phosphoserine binding activity; S-adenosyl-L-methionine binding activity; and mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity. Involved in mRNA methylation; negative regulation of translation; and positive regulation of translation. Located in intercellular bridge; microtubule cytoskeleton; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PCIF1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053909183).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCIF1	NM_022104.4	c.625A>G	p.Ile209Val	missense_variant	7/17	ENST00000372409.8	NP_071387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCIF1	ENST00000372409.8	c.625A>G	p.Ile209Val	missense_variant	7/17	1	NM_022104.4	ENSP00000361486.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461520 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.625A>G (p.I209V) alteration is located in exon 7 (coding exon 5) of the PCIF1 gene. This alteration results from a A to G substitution at nucleotide position 625, causing the isoleucine (I) at amino acid position 209 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.071
Sift	Benign	0.89	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.080
MutPred		0.20		Gain of catalytic residue at I209 (P = 0.0866);
MVP		0.15
MPC		1.4
ClinPred		0.62	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44569798;