Genetic Variant POM121L2:p.Ile969Val (chr6-27309266-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033482.4(POM121L2):c.2905A>G(p.Ile969Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 7.1e-7 ( 0 hom. )

Consequence

POM121L2
NM_033482.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Publications

0 publications found

Variant links:

Genes affected

POM121L2 (HGNC:13973): (POM121 transmembrane nucleoporin like 2) Predicted to enable nuclear localization sequence binding activity. Predicted to be a structural constituent of nuclear pore. Predicted to be involved in RNA export from nucleus and protein import into nucleus. Predicted to be part of nuclear pore. [provided by Alliance of Genome Resources, Apr 2022]

POM121L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07647261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POM121L2	NM_033482.4 link	c.2905A>G	p.Ile969Val	missense_variant	Exon 1 of 1	ENST00000444565.2	NP_258443.2	Q96KW2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POM121L2	ENST00000444565.2 link	c.2905A>G	p.Ile969Val	missense_variant	Exon 1 of 1	6	NM_033482.4	ENSP00000392726.1		Q96KW2
POM121L2	ENST00000429945.1 link	c.216+1831A>G		intron_variant	Intron 1 of 1	3		ENSP00000415181.1		H7C418

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399436

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31592

American (AMR)

AF:

0.00

AC:

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35740

South Asian (SAS)

AF:

0.00

AC:

AN:

79212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078956

Other (OTH)

AF:

0.00

AC:

AN:

58038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2905A>G (p.I969V) alteration is located in exon 1 (coding exon 1) of the POM121L2 gene. This alteration results from a A to G substitution at nucleotide position 2905, causing the isoleucine (I) at amino acid position 969 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

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.035

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.37

M_CAP

Benign

0.0021

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

PhyloP100

1.5

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.40

REVEL

Benign

0.018

Sift

Benign

0.061

Sift4G

Benign

0.20

Vest4

0.13

MutPred

0.22

Loss of methylation at K964 (P = 0.1106);

MVP

0.014

ClinPred

0.099

GERP RS

2.5

Varity_R

0.036

gMVP

0.037

Mutation Taster

=93/7

polymorphism

(source)

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

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6-27309266-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over