8-100705591-A-G

Position:

• chr8-100705591-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PP5

The NM_002568.4(PABPC1):​c.1685T>C​(p.Leu562Ser) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PABPC1 NM_002568.4 missense, splice_region
• Scores: Splicing: ADA: 0.6889
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• PP5: Variant 8-100705591-A-G is Pathogenic according to our data. Variant chr8-100705591-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1696850.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PABPC1	NM_002568.4	c.1685T>C	p.Leu562Ser	missense_variant, splice_region_variant	12/15	ENST00000318607.10
PABPC1	XM_005250861.4	c.1685T>C	p.Leu562Ser	missense_variant, splice_region_variant	12/15
PABPC1	XM_047421694.1	c.1685T>C	p.Leu562Ser	missense_variant, splice_region_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PABPC1	ENST00000318607.10	c.1685T>C	p.Leu562Ser	missense_variant, splice_region_variant	12/15	1	NM_002568.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00515 AC: 5343 AN: 1038258 Hom.: 0 Cov.: 27 AF XY: 0.00495 AC XY: 2603 AN XY: 525986

Gnomad4 AFR exome AF: 0.00666

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.000733

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000165 Hom.: 0

ExAC AF: 0.000503 AC: 61

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary artery atresia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Henan Key Laboratory of Chronic Disease Management, Central China Fuwai Hospital of Zhengzhou University, Fuwai Central China Cardiovascular Hospital & Central China Branch of National Center for Cardiovascular Diseases

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T;T;T;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.89
MVP		0.93
MPC		2.8
ClinPred		0.11	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.67
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: rs80006036; hg19: chr8-101717819; COSMIC: COSV59403232; COSMIC: COSV59403232;