16-88864261-C-T

Variant names:

• chr16-88864261-C-T
• rs768187856
• NM_001080487.4:c.773G>A

Variant summary

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

The NM_001080487.4(PABPN1L):​c.773G>A​(p.Arg258Gln) 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 1,400,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PABPN1L NM_001080487.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716

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]

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=0.16324198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPN1L	NM_001080487.4	c.773G>A	p.Arg258Gln	missense_variant	Exon 6 of 7	ENST00000419291.7	NP_001073956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPN1L	ENST00000419291.7	c.773G>A	p.Arg258Gln	missense_variant	Exon 6 of 7	1	NM_001080487.4	ENSP00000408598.2
PABPN1L	ENST00000411789.6	c.685G>A	p.Gly229Ser	missense_variant	Exon 5 of 6	1		ENSP00000405259.2
PABPN1L	ENST00000547152.1	c.666G>A	p.Pro222Pro	synonymous_variant	Exon 5 of 6	1		ENSP00000449247.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1400102 Hom.: 0 Cov.: 32 AF XY: 0.0000159 AC XY: 11 AN XY: 691424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000139

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000926

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000889 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.773G>A (p.R258Q) alteration is located in exon 6 (coding exon 6) of the PABPN1L gene. This alteration results from a G to A substitution at nucleotide position 773, causing the arginine (R) at amino acid position 258 to be replaced by a glutamine (Q). 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	0.097
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Benign	0.47	T
Polyphen		1.0	D
Vest4		0.16
MutPred		0.19		Gain of glycosylation at G229 (P = 0.0235);
MVP		0.14
ClinPred		0.83	D
GERP RS		1.2

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: rs768187856; hg19: chr16-88930669;