NM_016648.4:c.552+1G>T

Variant names:

• chr4-112646956-G-T
• rs200544616
• NM_016648.4:c.552+1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_016648.4(LARP7):​c.552+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,596,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: LARP7 NM_016648.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.16
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.094339624 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-112646956-G-T is Pathogenic according to our data. Variant chr4-112646956-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377284.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016648.4. 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.552+1G>T		splice_donor intron	N/A	NP_057732.2
	LARP7	NM_001370974.1		c.552+1G>T		splice_donor intron	N/A	NP_001357903.1
	LARP7	NM_001370975.1		c.552+1G>T		splice_donor intron	N/A	NP_001357904.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARP7	ENST00000344442.10	TSL:2 MANE Select	c.552+1G>T		splice_donor intron	N/A	ENSP00000344950.5
	LARP7	ENST00000509061.5	TSL:1	c.552+1G>T		splice_donor intron	N/A	ENSP00000422626.2
	LARP7	ENST00000509622.5	TSL:1	n.*311+1G>T		splice_donor intron	N/A	ENSP00000422451.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150302 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000905 AC: 21 AN: 232012 AF XY: 0.0000873

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: 0.000185

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000609 AC: 88 AN: 1446032 Hom.: 0 Cov.: 31 AF XY: 0.0000626 AC XY: 45 AN XY: 718856

African (AFR) AF: 0.00 AC: 0 AN: 32236

American (AMR) AF: 0.00 AC: 0 AN: 40536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25582

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 82004

European-Finnish (FIN) AF: 0.0000752 AC: 4 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.0000659 AC: 73 AN: 1107694

Other (OTH) AF: 0.000184 AC: 11 AN: 59654

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150302 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73406

African (AFR) AF: 0.00 AC: 0 AN: 40344

American (AMR) AF: 0.00 AC: 0 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000580 Hom.: 0

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
1	-	-	Microcephalic primordial dwarfism, Alazami type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Benign	0.00023	N
PhyloP100		9.2
GERP RS		5.9
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs200544616; hg19: chr4-113568112;