rs1554011754

chr4-112647351-GAACCCCAAAAGCAGTGCTCAAAGAAAAAGAAAAAACGGGACAGAGTTGAAGCATCTAGCTTACCTGAAGTCAGAACAGGGAAGAGGAAGAGAAGCAGCTCTGAAGATGCAGAATCCCTAGCTCCCCGATCAAAAGTAAAGAAAATTATTCAGAAAGACATCATTAAGGAAGCATCAGAAGCTTCCAAGGAAAATAGAGGTAAAACTACAAGGTTTTAATTAGATAAAACTAATTAATTTTAATTAATTAGTTTTTAATTAATTAGGTTTTAATTGGCTTCTGTTTCACCCATTTCACAGCCCCATGTCTTAACGGAGAGCTTTTTTATTTATTTCAAGATATAGAAATCTCTACTGAAGAGGAAAAGGATACTGGAGATCTAAAAGATAGCTCTCTCTTGAAAACAAAAAGGAAACATAAGAAAAAACATAAAGAGAGACATAAAATGGGAGAAGAAGTTATACCATTAAGAGTGCTATCAAAGTAAGTCTGTGGTTTAAATTCTGTCATTGGCTTAACAATCCATCACCATTGCTAAAGTGCAATTCCAATTTATATTCAACAGAGTTGCATATTAGCAACAGTAATGGCCTGTAGCCAAGAACTGCACACAGTGTGGGCGTTAACGCAATTGCTGATTAGGTAGGAACCACCACACTCAAACATGGAAGCACTTATTTTTGTCATGTCACAGCAAGTGCCTCCATGTTAAAGTAGAGGGGGCCCCTTAACAGATGTAAAAATACAA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_016648.4(LARP7):c.802_1142+267del variant causes a splice acceptor, splice donor, splice donor 5th base, coding sequence, intron change. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARP7 NM_016648.4 splice_acceptor, splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.88

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]

MIR302D (HGNC:31765): (microRNA 302d) 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]

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]

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.20011435 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 4-112647351-GAACCCCAAAAGCAGTGCTCAAAGAAAAAGAAAAAACGGGACAGAGTTGAAGCATCTAGCTTACCTGAAGTCAGAACAGGGAAGAGGAAGAGAAGCAGCTCTGAAGATGCAGAATCCCTAGCTCCCCGATCAAAAGTAAAGAAAATTATTCAGAAAGACATCATTAAGGAAGCATCAGAAGCTTCCAAGGAAAATAGAGGTAAAACTACAAGGTTTTAATTAGATAAAACTAATTAATTTTAATTAATTAGTTTTTAATTAATTAGGTTTTAATTGGCTTCTGTTTCACCCATTTCACAGCCCCATGTCTTAACGGAGAGCTTTTTTATTTATTTCAAGATATAGAAATCTCTACTGAAGAGGAAAAGGATACTGGAGATCTAAAAGATAGCTCTCTCTTGAAAACAAAAAGGAAACATAAGAAAAAACATAAAGAGAGACATAAAATGGGAGAAGAAGTTATACCATTAAGAGTGCTATCAAAGTAAGTCTGTGGTTTAAATTCTGTCATTGGCTTAACAATCCATCACCATTGCTAAAGTGCAATTCCAATTTATATTCAACAGAGTTGCATATTAGCAACAGTAATGGCCTGTAGCCAAGAACTGCACACAGTGTGGGCGTTAACGCAATTGCTGATTAGGTAGGAACCACCACACTCAAACATGGAAGCACTTATTTTTGTCATGTCACAGCAAGTGCCTCCATGTTAAAGTAGAGGGGGCCCCTTAACAGATGTAAAAATACAA-G is Pathogenic according to our data. Variant chr4-112647351-GAACCCCAAAAGCAGTGCTCAAAGAAAAAGAAAAAACGGGACAGAGTTGAAGCATCTAGCTTACCTGAAGTCAGAACAGGGAAGAGGAAGAGAAGCAGCTCTGAAGATGCAGAATCCCTAGCTCCCCGATCAAAAGTAAAGAAAATTATTCAGAAAGACATCATTAAGGAAGCATCAGAAGCTTCCAAGGAAAATAGAGGTAAAACTACAAGGTTTTAATTAGATAAAACTAATTAATTTTAATTAATTAGTTTTTAATTAATTAGGTTTTAATTGGCTTCTGTTTCACCCATTTCACAGCCCCATGTCTTAACGGAGAGCTTTTTTATTTATTTCAAGATATAGAAATCTCTACTGAAGAGGAAAAGGATACTGGAGATCTAAAAGATAGCTCTCTCTTGAAAACAAAAAGGAAACATAAGAAAAAACATAAAGAGAGACATAAAATGGGAGAAGAAGTTATACCATTAAGAGTGCTATCAAAGTAAGTCTGTGGTTTAAATTCTGTCATTGGCTTAACAATCCATCACCATTGCTAAAGTGCAATTCCAATTTATATTCAACAGAGTTGCATATTAGCAACAGTAATGGCCTGTAGCCAAGAACTGCACACAGTGTGGGCGTTAACGCAATTGCTGATTAGGTAGGAACCACCACACTCAAACATGGAAGCACTTATTTTTGTCATGTCACAGCAAGTGCCTCCATGTTAAAGTAGAGGGGGCCCCTTAACAGATGTAAAAATACAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 211371.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARP7	NM_016648.4	c.802_1142+267del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/13	ENST00000344442.10
MIR302D	NR_029859.1			transcript_ablation	1/1
MIR367	NR_029860.1			transcript_ablation	1/1
MIR302CHG	NR_146092.1	n.147+414_148-384del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARP7	ENST00000344442.10	c.802_1142+267del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	7/13	2	NM_016648.4	P4
MIR302D	ENST00000362275.1			transcript_ablation	1/1
MIR367	ENST00000362299.1			transcript_ablation	1/1
MIR302CHG	ENST00000510655.1	n.147+414_148-384del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephalic primordial dwarfism, Alazami type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 02, 2015

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554011754; hg19: chr4-113568507;