rs1057519017

Variant names:

• chr4-112647714-A-AAAAGGAT
• rs1057519017
• NM_016648.4:c.1024_1030dupAAGGATA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001370974.1(LARP7):​c.1063_1069dupAAGGATA​(p.Thr357LysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARP7 NM_001370974.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.154
• Publications: 7 publications found

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]

MIR302CHG (HGNC:41070): (miR-302/367 cluster host gene)

MIR367 (HGNC:31781): (microRNA 367) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-112647714-A-AAAAGGAT is Pathogenic according to our data. Variant chr4-112647714-A-AAAAGGAT is described in ClinVar as Pathogenic. ClinVar VariationId is 39615.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370974.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARP7	NM_016648.4	MANE Select	c.1024_1030dupAAGGATA	p.Thr344LysfsTer9	frameshift	Exon 8 of 13	NP_057732.2
	LARP7	NM_001370974.1		c.1063_1069dupAAGGATA	p.Thr357LysfsTer9	frameshift	Exon 8 of 13	NP_001357903.1
	LARP7	NM_001370975.1		c.1063_1069dupAAGGATA	p.Thr357LysfsTer9	frameshift	Exon 8 of 13	NP_001357904.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARP7	ENST00000344442.10	TSL:2 MANE Select	c.1024_1030dupAAGGATA	p.Thr344LysfsTer9	frameshift	Exon 8 of 13	ENSP00000344950.5
	LARP7	ENST00000509061.5	TSL:1	c.1024_1030dupAAGGATA	p.Thr344LysfsTer9	frameshift	Exon 10 of 15	ENSP00000422626.2
	LARP7	ENST00000509622.5	TSL:1	n.*783_*789dupAAGGATA		non_coding_transcript_exon	Exon 8 of 13	ENSP00000422451.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	Microcephalic primordial dwarfism, Alazami type (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.15
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519017; hg19: chr4-113568870;