20-44916771-C-T

Position:

• chr20-44916771-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001372179.1(PABPC1L):​c.403C>T​(p.His135Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000014 (0 hom.)
• Consequence: PABPC1L NM_001372179.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

Genes affected

PABPC1L (HGNC:15797): (poly(A) binding protein cytoplasmic 1 like) This gene belongs to the polyadenylate-binding protein type-1 family of proteins. Members of this family bind to the polyA tails of mRNAs to regulate mRNA stability and translation. The mouse ortholog of this gene is required for female fertility. In human, expression of a functional protein is regulated by alternative splicing. The protein-coding splice variant for this gene is abundantly expressed in human oocytes, while a noncoding splice variant subject to nonsense-mediated decay is the predominant splice variant expressed in somatic tissues. [provided by RefSeq, Aug 2019]

PABPC1L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17318708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PABPC1L	NM_001372179.1	c.403C>T	p.His135Tyr	missense_variant	3/15	ENST00000217073.7	NP_001359108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PABPC1L	ENST00000217073.7	c.403C>T	p.His135Tyr	missense_variant	3/15	5	NM_001372179.1	ENSP00000217073.3
PABPC1L	ENST00000537323.5	n.403C>T		non_coding_transcript_exon_variant	3/14	1		ENSP00000445661.1
PABPC1L	ENST00000255136.8	c.403C>T	p.His135Tyr	missense_variant	3/15	5		ENSP00000255136.3
PABPC1L	ENST00000217074.9	n.367-2135C>T		intron_variant		5		ENSP00000217074.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The c.403C>T (p.H135Y) alteration is located in exon 3 (coding exon 3) of the PABPC1L gene. This alteration results from a C to T substitution at nucleotide position 403, causing the histidine (H) at amino acid position 135 to be replaced by a tyrosine (Y). 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	0.084
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.070	.;T;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.87	.;D;D;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.41	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.071	T;T;T;T
Sift4G	Uncertain	0.045	D;T;D;T
Polyphen		0.0080	.;B;.;B
Vest4		0.41
MutPred		0.30		Loss of catalytic residue at H135 (P = 0.0247);Loss of catalytic residue at H135 (P = 0.0247);Loss of catalytic residue at H135 (P = 0.0247);Loss of catalytic residue at H135 (P = 0.0247);
MVP		0.82
MPC		0.29
ClinPred		0.099	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43545412;