Genetic Variant PABPN1L:p.Arg268His (chr16-88863790-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080487.4(PABPN1L):c.803G>A(p.Arg268His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,536,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

PABPN1L
NM_001080487.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.380

Variant links:

Genes affected

PABPN1L (HGNC:37237): (PABPN1 like, cytoplasmic) Predicted to enable RNA binding activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PABPN1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.008474797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1L	NM_001080487.4 link	c.803G>A	p.Arg268His	missense_variant	Exon 7 of 7	ENST00000419291.7	NP_001073956.2	A6NDY0-1B6RF28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PABPN1L	ENST00000419291.7 link	c.803G>A	p.Arg268His	missense_variant	Exon 7 of 7	1	NM_001080487.4	ENSP00000408598.2	A6NDY0-1
PABPN1L	ENST00000411789.6 link	c.715G>A	p.Val239Met	missense_variant	Exon 6 of 6	1		ENSP00000405259.2	A6NDY0-2
PABPN1L	ENST00000547152.1 link	c.696G>A	p.Pro232Pro	synonymous_variant	Exon 6 of 6	1		ENSP00000449247.1	A0A1C7CYY8

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000190

AC:

AN:

136976

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

74434

show subpopulations

Gnomad AFR exome

AF:

0.000774

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00143

Gnomad SAS exome

AF:

0.0000889

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.000477

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1383658

Hom.:

Cov.:

AF XY:

0.0000557

AC XY:

AN XY:

682762

show subpopulations

Gnomad4 AFR exome

AF:

0.000665

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000840

Gnomad4 SAS exome

AF:

0.0000884

Gnomad4 FIN exome

AF:

0.0000295

Gnomad4 NFE exome

AF:

0.00000742

Gnomad4 OTH exome

AF:

0.000328

GnomAD4 genome

AF:

0.000315

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000142

AC:

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803G>A (p.R268H) alteration is located in exon 7 (coding exon 7) of the PABPN1L gene. This alteration results from a G to A substitution at nucleotide position 803, causing the arginine (R) at amino acid position 268 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.46

M_CAP

Benign

0.023

MetaRNN

Benign

0.0085

MetaSVM

Benign

-0.96

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.019

Sift

Benign

0.076

Sift4G

Benign

0.13

Polyphen

0.035

Vest4

0.17

MutPred

0.33

Loss of methylation at R268 (P = 0.0071);

MVP

0.055

MPC

0.010

ClinPred

0.016

GERP RS

-0.32

Varity_R

0.062

gMVP

0.60

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over