1-156225640-C-A

Variant names:

• chr1-156225640-C-A
• rs1055553309
• NM_007221.4:c.162-6680C>A

Variant summary

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

The NM_001199654.2(PMF1):​c.245C>A​(p.Ala82Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,409,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A82V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PMF1 NM_001199654.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0900
• Publications: 0 publications found

Genes affected

PMF1 (HGNC:9112): (polyamine modulated factor 1) Enables leucine zipper domain binding activity and transcription coactivator activity. Involved in chromosome segregation. Located in Golgi apparatus; kinetochore; and nucleoplasm. Part of MIS12/MIND type complex. Implicated in bladder carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

PMF1-BGLAP (HGNC:42953): (PMF1-BGLAP readthrough) This locus represents naturally occurring read-through transcription between the neighboring PMF1 (polyamine-modulated factor 1) and BGLAP (bone gamma-carboxyglutamate Gla protein) genes on chromosome 1. Alternative splicing results in multiple transcript variants encoding isoforms that share sequence identity with the upstream gene product, but they contain distinct C-termini due to frameshifts versus the downstream gene coding sequence. [provided by RefSeq, Dec 2010]

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=0.28274852).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199654.2. 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
	PMF1	NM_007221.4	MANE Select	c.162-6680C>A		intron	N/A	NP_009152.2	Q6P1K2-1
	PMF1	NM_001199654.2		c.245C>A	p.Ala82Glu	missense	Exon 2 of 5	NP_001186583.1	Q6P1K2-2
	PMF1	NM_001393910.1		c.245C>A	p.Ala82Glu	missense	Exon 2 of 5	NP_001380839.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMF1	ENST00000368277.3	TSL:1 MANE Select	c.162-6680C>A		intron	N/A	ENSP00000357260.3	Q6P1K2-1
	PMF1-BGLAP	ENST00000490491.5	TSL:2	c.162-6680C>A		intron	N/A	ENSP00000475561.1	U3KQ54
	PMF1-BGLAP	ENST00000320139.5	TSL:1	c.162-6680C>A		intron	N/A	ENSP00000324909.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409396 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 696384

African (AFR) AF: 0.00 AC: 0 AN: 32198

American (AMR) AF: 0.0000269 AC: 1 AN: 37184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.00 AC: 0 AN: 36940

South Asian (SAS) AF: 0.00 AC: 0 AN: 80034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084580

Other (OTH) AF: 0.00 AC: 0 AN: 58444

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.0
DANN	Benign	0.74
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.090
PROVEAN	Benign	0.24	N
REVEL	Benign	0.075
Sift	Benign	0.40	T
Sift4G	Benign	0.067	T
Vest4		0.57
MutPred		0.56		Loss of MoRF binding (P = 0.0294)
MVP		0.055
ClinPred		0.028	T
GERP RS		0.029
gMVP		0.76
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs1055553309; hg19: chr1-156195431;