4-112644730-AAAG-A

Variant names:

• chr4-112644730-AAAG-A
• rs570445594
• NM_016648.4:c.65_67delAAG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_016648.4(LARP7):​c.65_67delAAG​(p.Glu22del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,611,350 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (21 hom.)
• Consequence: LARP7 NM_016648.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.45
• 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]

LARP7 Gene-Disease associations (from GenCC):

• microcephalic primordial dwarfism, Alazami type

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016648.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 4-112644730-AAAG-A is Benign according to our data. Variant chr4-112644730-AAAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 777974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00291 (442/152014) while in subpopulation NFE AF = 0.00539 (366/67954). AF 95% confidence interval is 0.00493. There are 0 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARP7	NM_016648.4	MANE Select	c.65_67delAAG	p.Glu22del	disruptive_inframe_deletion	Exon 2 of 13	NP_057732.2	Q4G0J3-1
	LARP7	NM_001370974.1		c.65_67delAAG	p.Glu22del	disruptive_inframe_deletion	Exon 2 of 13	NP_001357903.1	A0A8Q3SHN7
	LARP7	NM_001370975.1		c.65_67delAAG	p.Glu22del	disruptive_inframe_deletion	Exon 2 of 13	NP_001357904.1	A0A8Q3SHN7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARP7	ENST00000344442.10	TSL:2 MANE Select	c.65_67delAAG	p.Glu22del	disruptive_inframe_deletion	Exon 2 of 13	ENSP00000344950.5	Q4G0J3-1
	LARP7	ENST00000509061.5	TSL:1	c.65_67delAAG	p.Glu22del	disruptive_inframe_deletion	Exon 4 of 15	ENSP00000422626.2	Q4G0J3-1
	LARP7	ENST00000509622.5	TSL:1	n.65_67delAAG		non_coding_transcript_exon	Exon 2 of 13	ENSP00000422451.1	D6RBH8

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 442 AN: 151896 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00273 AC: 678 AN: 248796 AF XY: 0.00296

Gnomad AFR exome AF: 0.000970

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.00475

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00457 AC: 6665 AN: 1459336 Hom.: 21 AF XY: 0.00440 AC XY: 3194 AN XY: 726050

African (AFR) AF: 0.000897 AC: 30 AN: 33444

American (AMR) AF: 0.000829 AC: 37 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.000921 AC: 24 AN: 26048

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39562

South Asian (SAS) AF: 0.00172 AC: 148 AN: 86022

European-Finnish (FIN) AF: 0.000600 AC: 32 AN: 53324

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.00555 AC: 6157 AN: 1110278

Other (OTH) AF: 0.00378 AC: 228 AN: 60264

GnomAD4 genome AF: 0.00291 AC: 442 AN: 152014 Hom.: 0 Cov.: 31 AF XY: 0.00260 AC XY: 193 AN XY: 74340

African (AFR) AF: 0.00111 AC: 46 AN: 41546

American (AMR) AF: 0.000720 AC: 11 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00539 AC: 366 AN: 67954

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00287

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	LARP7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs570445594; hg19: chr4-113565886; COSMIC: COSV60521179; COSMIC: COSV60521179;