4-128098248-A-C

Position:

• chr4-128098248-A-C

Variant summary

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

The NM_018078.4(LARP1B):​c.731A>C​(p.Glu244Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LARP1B NM_018078.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705

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]

LARP1B (HGNC:):

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=0.10163435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARP1B	NM_018078.4	c.731A>C	p.Glu244Ala	missense_variant	8/20	ENST00000326639.11	NP_060548.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARP1B	ENST00000326639.11	c.731A>C	p.Glu244Ala	missense_variant	8/20	5	NM_018078.4	ENSP00000321997.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461452 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727054

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.731A>C (p.E244A) alteration is located in exon 8 (coding exon 6) of the LARP1B gene. This alteration results from a A to C substitution at nucleotide position 731, causing the glutamic acid (E) at amino acid position 244 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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.0025	T;.;.;.;T;.;.;.
Eigen	Benign	0.025
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.38	N;.;.;N;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.21	N;N;N;N;N;.;.;.
REVEL	Benign	0.066
Sift	Benign	0.86	T;T;T;T;T;.;.;.
Sift4G	Benign	0.93	T;T;T;T;T;.;.;.
Polyphen		0.0	B;.;.;B;B;.;.;.
Vest4		0.18
MutPred		0.42		Loss of solvent accessibility (P = 0.0404);Loss of solvent accessibility (P = 0.0404);.;Loss of solvent accessibility (P = 0.0404);Loss of solvent accessibility (P = 0.0404);.;.;.;
MVP		0.38
MPC		0.17
ClinPred		0.079	T
GERP RS		5.0
Varity_R		0.054
gMVP		0.28

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: rs1778787142; hg19: chr4-129019403;