rs1269618076

Variant names:

• chr4-112644734-A-T
• rs1269618076
• NM_016648.4:c.65A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016648.4(LARP7):​c.65A>T​(p.Glu22Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,608,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E22K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LARP7 NM_016648.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.96
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21693537).

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.65A>T	p.Glu22Val	missense	Exon 2 of 13	NP_057732.2	Q4G0J3-1
	LARP7	NM_001370974.1		c.65A>T	p.Glu22Val	missense	Exon 2 of 13	NP_001357903.1	A0A8Q3SHN7
	LARP7	NM_001370975.1		c.65A>T	p.Glu22Val	missense	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.65A>T	p.Glu22Val	missense	Exon 2 of 13	ENSP00000344950.5	Q4G0J3-1
	LARP7	ENST00000509061.5	TSL:1	c.65A>T	p.Glu22Val	missense	Exon 4 of 15	ENSP00000422626.2	Q4G0J3-1
	LARP7	ENST00000509622.5	TSL:1	n.65A>T		non_coding_transcript_exon	Exon 2 of 13	ENSP00000422451.1	D6RBH8

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457516 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725248

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108550

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151028 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73828

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10466

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67240

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
Eigen	Benign	0.087
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.086
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0060	B
Vest4		0.29
MutPred		0.34		Loss of helix (P = 0.0304)
MVP		0.50
MPC		0.12
ClinPred		0.97	D
GERP RS		3.8
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.36
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1269618076; hg19: chr4-113565890;