Genetic Variant PABPN1L:p.Ala204Thr (chr16-88864897-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001080487.4(PABPN1L):c.610G>A(p.Ala204Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000525 in 1,561,556 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 1 hom. )

Consequence

PABPN1L
NM_001080487.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1L	NM_001080487.4 link	c.610G>A	p.Ala204Thr	missense_variant	Exon 5 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.610G>A	p.Ala204Thr	missense_variant	Exon 5 of 7	1	NM_001080487.4	ENSP00000408598.2	A6NDY0-1
PABPN1L	ENST00000547152.1 link	c.503G>A	p.Arg168His	missense_variant	Exon 4 of 6	1		ENSP00000449247.1	A0A1C7CYY8
PABPN1L	ENST00000411789.6 link	c.566+125G>A		intron_variant	Intron 4 of 5	1		ENSP00000405259.2	A6NDY0-2

Frequencies

GnomAD3 genomes

AF:

0.0000203

AC:

AN:

147970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000668

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000447

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

244262

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

133616

show subpopulations

Gnomad AFR exome

AF:

0.0000687

Gnomad AMR exome

AF:

0.000848

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000264

Gnomad FIN exome

AF:

0.0000938

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000559

AC:

AN:

1413462

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

702840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000957

Gnomad4 AMR exome

AF:

0.000789

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000397

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.00000554

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.0000203

AC:

AN:

148094

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

72352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000667

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000447

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000764

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.610G>A (p.A204T) alteration is located in exon 5 (coding exon 5) of the PABPN1L gene. This alteration results from a G to A substitution at nucleotide position 610, causing the alanine (A) at amino acid position 204 to be replaced by a threonine (T). 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

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.63

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

4.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.45

MutPred

0.79

Gain of glycosylation at A204 (P = 0.0905);

MVP

0.76

MPC

0.065

ClinPred

0.63

GERP RS

4.4

Varity_R

0.59

gMVP

0.74

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