Genetic Variant PABPN1L:p.Gly235Arg (chr16-88864331-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001080487.4(PABPN1L):c.703G>A(p.Gly235Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00161 in 1,555,466 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

PABPN1L
NM_001080487.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073765874).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1L	NM_001080487.4 link	c.703G>A	p.Gly235Arg	missense_variant	Exon 6 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.703G>A	p.Gly235Arg	missense_variant	Exon 6 of 7	1	NM_001080487.4	ENSP00000408598.2	A6NDY0-1
PABPN1L	ENST00000547152.1 link	c.596G>A	p.Arg199Gln	missense_variant	Exon 5 of 6	1		ENSP00000449247.1	A0A1C7CYY8
PABPN1L	ENST00000411789.6 link	c.615G>A	p.Ala205Ala	synonymous_variant	Exon 5 of 6	1		ENSP00000405259.2	A6NDY0-2

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000915

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00101

AC:

161

AN:

159234

Hom.:

AF XY:

0.000908

AC XY:

AN XY:

84824

show subpopulations

Gnomad AFR exome

AF:

0.000354

Gnomad AMR exome

AF:

0.000821

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000739

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.000674

GnomAD4 exome

AF:

0.00167

AC:

2337

AN:

1403166

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1146

AN XY:

692642

show subpopulations

Gnomad4 AFR exome

AF:

0.000440

Gnomad4 AMR exome

AF:

0.000874

Gnomad4 ASJ exome

AF:

0.0000396

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.000667

Gnomad4 FIN exome

AF:

0.000123

Gnomad4 NFE exome

AF:

0.00202

Gnomad4 OTH exome

AF:

0.000739

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152300

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000914

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.00115

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000268

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.000672

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703G>A (p.G235R) alteration is located in exon 6 (coding exon 6) of the PABPN1L gene. This alteration results from a G to A substitution at nucleotide position 703, causing the glycine (G) at amino acid position 235 to be replaced by an arginine (R). 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.048

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.045

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.48

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.43

Sift

Benign

0.057

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.76

MutPred

0.30

Gain of solvent accessibility (P = 0.006);

MVP

0.62

MPC

0.016

ClinPred

0.086

GERP RS

5.0

Varity_R

0.48

gMVP

0.67

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

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