chr4-112649597-TA-T

Variant names:

• chr4-112649597-TA-T
• rs750946801
• NM_016648.4:c.1213delA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000344442.10(LARP7):​c.1213delA​(p.Thr405GlnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,546 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LARP7 ENST00000344442.10 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 6 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)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000344442.10. 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.1213delA	p.Thr405GlnfsTer5	frameshift	Exon 9 of 13	NP_057732.2
	LARP7	NM_001370974.1		c.1252delA	p.Thr418GlnfsTer5	frameshift	Exon 9 of 13	NP_001357903.1
	LARP7	NM_001370975.1		c.1252delA	p.Thr418GlnfsTer5	frameshift	Exon 9 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.1213delA	p.Thr405GlnfsTer5	frameshift	Exon 9 of 13	ENSP00000344950.5
	LARP7	ENST00000509061.5	TSL:1	c.1213delA	p.Thr405GlnfsTer5	frameshift	Exon 11 of 15	ENSP00000422626.2
	LARP7	ENST00000509622.5	TSL:1	n.*972delA		non_coding_transcript_exon	Exon 9 of 13	ENSP00000422451.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000839 AC: 2 AN: 238496 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000934

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451546 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.00 AC: 0 AN: 44004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105690

Other (OTH) AF: 0.00 AC: 0 AN: 59848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

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

Other links and lift over

dbSNP: rs750946801; hg19: chr4-113570753; COSMIC: COSV60520263; COSMIC: COSV60520263;