4-128091111-C-T

Variant names:

• chr4-128091111-C-T
• rs755884569
• NM_018078.4:c.469C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001350531.2(LARP1B):​c.-89C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: LARP1B NM_001350531.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.807

Genes affected

LARP1B (HGNC:24704): (La ribonucleoprotein 1B) This gene encodes a protein containing domains found in the La related protein of Drosophila melanogaster. La motif-containing proteins are thought to be RNA-binding proteins, where the La motif and adjacent amino acids fold into an RNA recognition motif. The La motif is also found in proteins unrelated to the La protein. Alternative splicing has been observed at this locus and multiple variants, encoding distinct isoforms, are described. Additional splice variation has been identified but the full-length nature of these transcripts has not been determined. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31330675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARP1B	NM_018078.4	c.469C>T	p.Arg157Trp	missense_variant	Exon 6 of 20	ENST00000326639.11	NP_060548.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARP1B	ENST00000326639.11	c.469C>T	p.Arg157Trp	missense_variant	Exon 6 of 20	5	NM_018078.4	ENSP00000321997.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151904 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251412 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135868

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461354 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32 AN XY: 727004

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: 0.0000594

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151904 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74144

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469C>T (p.R157W) alteration is located in exon 6 (coding exon 4) of the LARP1B gene. This alteration results from a C to T substitution at nucleotide position 469, causing the arginine (R) at amino acid position 157 to be replaced by a tryptophan (W). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.096	T;.;.;.;T;.;.;.
Eigen	Benign	0.043
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;.;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.015	D;D;D;D;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;D;D;.;.;.
Vest4		0.40
MutPred		0.33		Loss of methylation at R157 (P = 0.0024);Loss of methylation at R157 (P = 0.0024);.;Loss of methylation at R157 (P = 0.0024);Loss of methylation at R157 (P = 0.0024);.;.;.;
MVP		0.55
MPC		0.28
ClinPred		0.93	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.46

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: rs755884569; hg19: chr4-129012266; COSMIC: COSV52803646;