Variant 4-112646348-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016648.4(LARP7):c.203-3T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,348,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

LARP7
NM_016648.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9957

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 0.384

Variant links:

Genes affected

LARP7 (HGNC:24912): (La ribonucleoprotein 7, transcriptional regulator) This gene encodes a protein which is found in the 7SK snRNP (small nuclear ribonucleoprotein). This snRNP complex inhibits a cyclin-dependent kinase, positive transcription elongation factor b, which is required for paused RNA polymerase II at a promoter to begin transcription elongation. A pseudogene of this gene is located on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

LARP7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARP7	NM_016648.4 linkuse as main transcript	c.203-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000344442.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARP7	ENST00000344442.10 linkuse as main transcript	c.203-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_016648.4	P4	Q4G0J3-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.000478

GnomAD3 exomes

AF:

0.000289

AC:

AN:

228530

Hom.:

AF XY:

0.000225

AC XY:

AN XY:

124360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00183

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:

0.0000939

Gnomad OTH exome

AF:

0.000546

GnomAD4 exome

AF:

0.000105

AC:

125

AN:

1196136

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

607446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00174

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:

0.0000589

Gnomad4 OTH exome

AF:

0.0000973

GnomAD4 genome

AF:

0.000118

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000915

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:

0.000473

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2021	This sequence change falls in intron 2 of the LARP7 gene. It does not directly change the encoded amino acid sequence of the LARP7 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201651306, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with LARP7-related conditions. ClinVar contains an entry for this variant (Variation ID: 452711). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2017	The c.203-3 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.203-3 T>G variant is observed in 50/29132 (0.2%) alleles from individuals of Latino background (Lek et al., 2016). This variant is predicted to damage or destroy the splice acceptor site in intron 2, and is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Additionally, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

LARP7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.70

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over