4-128098188-A-G

Position:

• chr4-128098188-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018078.4(LARP1B):​c.671A>G​(p.Glu224Gly) 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARP1B NM_018078.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.97

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARP1B	NM_018078.4	c.671A>G	p.Glu224Gly	missense_variant, splice_region_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.671A>G	p.Glu224Gly	missense_variant, splice_region_variant	8/20	5	NM_018078.4	ENSP00000321997.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Feb 21, 2024

The c.671A>G (p.E224G) alteration is located in exon 8 (coding exon 6) of the LARP1B gene. This alteration results from a A to G substitution at nucleotide position 671, causing the glutamic acid (E) at amino acid position 224 to be replaced by a glycine (G). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.;.;.;T;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.5	H;.;.;H;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;.;.;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;D;D;.;.;.
Vest4		0.89
MutPred		0.84		Gain of glycosylation at Y226 (P = 0.0591);Gain of glycosylation at Y226 (P = 0.0591);.;Gain of glycosylation at Y226 (P = 0.0591);Gain of glycosylation at Y226 (P = 0.0591);.;.;.;
MVP		0.80
MPC		0.69
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-129019343;