4-112644860-C-G

Variant names:

• chr4-112644860-C-G
• rs758628046
• NM_016648.4:c.191C>G

Variant summary

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

The NM_016648.4(LARP7):​c.191C>G​(p.Ser64Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,626 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S64Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LARP7 NM_016648.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.191C>G	p.Ser64Cys	missense	Exon 2 of 13	NP_057732.2	Q4G0J3-1
	LARP7	NM_001370974.1		c.191C>G	p.Ser64Cys	missense	Exon 2 of 13	NP_001357903.1	A0A8Q3SHN7
	LARP7	NM_001370975.1		c.191C>G	p.Ser64Cys	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.191C>G	p.Ser64Cys	missense	Exon 2 of 13	ENSP00000344950.5	Q4G0J3-1
	LARP7	ENST00000509061.5	TSL:1	c.191C>G	p.Ser64Cys	missense	Exon 4 of 15	ENSP00000422626.2	Q4G0J3-1
	LARP7	ENST00000509622.5	TSL:1	n.99+92C>G		intron	N/A	ENSP00000422451.1	D6RBH8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000431 AC: 1 AN: 232194 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418626 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705310

African (AFR) AF: 0.00 AC: 0 AN: 32234

American (AMR) AF: 0.00 AC: 0 AN: 41650

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 25022

East Asian (EAS) AF: 0.00 AC: 0 AN: 37942

South Asian (SAS) AF: 0.00 AC: 0 AN: 78914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087654

Other (OTH) AF: 0.00 AC: 0 AN: 58050

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.53		Loss of disorder (P = 8e-04)
MVP		0.69
MPC		0.12
ClinPred		0.89	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.46
Mutation Taster		=38/62	disease causing

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: rs758628046; hg19: chr4-113566016;