4-134199984-T-C

Variant names:

• chr4-134199984-T-C
• rs1333293489
• NM_001114734.2:c.1036A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001114734.2(PABPC4L):​c.1036A>G​(p.Thr346Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,399,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T346S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PABPC4L NM_001114734.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

Genes affected

PABPC4L (HGNC:31955): (poly(A) binding protein cytoplasmic 4 like) Predicted to enable mRNA 3'-UTR binding activity; poly(A) binding activity; and poly(U) RNA binding activity. Predicted to be part of ribonucleoprotein complex. Predicted to be active in cytoplasmic stress granule; cytosol; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000251199 (HGNC:):

ACMG classification

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=0.05002448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPC4L	NM_001114734.2	c.1036A>G	p.Thr346Ala	missense_variant	Exon 2 of 2	ENST00000421491.4	NP_001108206.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPC4L	ENST00000421491.4	c.1036A>G	p.Thr346Ala	missense_variant	Exon 2 of 2	3	NM_001114734.2	ENSP00000463233.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000325 AC: 5 AN: 154050 Hom.: 0 AF XY: 0.0000245 AC XY: 2 AN XY: 81746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.000262

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1399384 Hom.: 0 Cov.: 42 AF XY: 0.0000145 AC XY: 10 AN XY: 690200

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.00000741

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1210A>G (p.T404A) alteration is located in exon 2 (coding exon 1) of the PABPC4L gene. This alteration results from a A to G substitution at nucleotide position 1210, causing the threonine (T) at amino acid position 404 to be replaced by an alanine (A). 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	0.061
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.1
DANN	Benign	0.27
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.050	T
MutationAssessor	Benign	-0.17	N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.41
GERP RS		-4.6
Varity_R		0.036
gMVP		0.57

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

Other links and lift over

dbSNP: rs1333293489; hg19: chr4-135121139;