rs202060459

Variant names:

• chr8-100712378-G-A
• rs202060459
• NM_002568.4:c.956C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_002568.4(PABPC1):​c.956C>T​(p.Thr319Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PABPC1 NM_002568.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 9.94
• Publications: 29 publications found

Genes affected

PABPC1 (HGNC:8554): (poly(A) binding protein cytoplasmic 1) This gene encodes a poly(A) binding protein. The protein shuttles between the nucleus and cytoplasm and binds to the 3' poly(A) tail of eukaryotic messenger RNAs via RNA-recognition motifs. The binding of this protein to poly(A) promotes ribosome recruitment and translation initiation; it is also required for poly(A) shortening which is the first step in mRNA decay. The gene is part of a small gene family including three protein-coding genes and several pseudogenes.[provided by RefSeq, Aug 2010]

ENSG00000310385 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• BP6: Variant 8-100712378-G-A is Benign according to our data. Variant chr8-100712378-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2681460.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002568.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABPC1	NM_002568.4	MANE Select	c.956C>T	p.Thr319Ile	missense	Exon 7 of 15	NP_002559.2
	PABPC1	NM_001438282.1		c.956C>T	p.Thr319Ile	missense	Exon 7 of 15	NP_001425211.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABPC1	ENST00000318607.10	TSL:1 MANE Select	c.956C>T	p.Thr319Ile	missense	Exon 7 of 15	ENSP00000313007.5	P11940-1
	PABPC1	ENST00000610907.2	TSL:1	c.812C>T	p.Thr271Ile	missense	Exon 7 of 14	ENSP00000478108.2	A0A087WTT1
	PABPC1	ENST00000900770.1		c.1049C>T	p.Thr350Ile	missense	Exon 8 of 16	ENSP00000570829.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000174 AC: 2 AN: 1152718 Hom.: 0 Cov.: 27 AF XY: 0.00000175 AC XY: 1 AN XY: 572684

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24596

American (AMR) AF: 0.00 AC: 0 AN: 31628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21092

East Asian (EAS) AF: 0.00 AC: 0 AN: 37016

South Asian (SAS) AF: 0.00 AC: 0 AN: 66498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4718

European-Non Finnish (NFE) AF: 0.00000231 AC: 2 AN: 867628

Other (OTH) AF: 0.00 AC: 0 AN: 48732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EBV-positive nodal T- and NK-cell lymphoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.77
MVP		0.88
MPC		2.3
ClinPred		0.98	D
GERP RS		5.7
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.74
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs202060459; hg19: chr8-101724606; COSMIC: COSV59397639; COSMIC: COSV59397639;