rs758628046

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-112644860-C-A
• chr4-112644860-C-G
• chr4-112644860-C-T

Variant summary

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

The NM_016648.4(LARP7):​c.191C>A​(p.Ser64Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,418,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LARP7 NM_016648.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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>A	p.Ser64Tyr	missense	Exon 2 of 13	NP_057732.2	Q4G0J3-1
	LARP7	NM_001370974.1		c.191C>A	p.Ser64Tyr	missense	Exon 2 of 13	NP_001357903.1	A0A8Q3SHN7
	LARP7	NM_001370975.1		c.191C>A	p.Ser64Tyr	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>A	p.Ser64Tyr	missense	Exon 2 of 13	ENSP00000344950.5	Q4G0J3-1
	LARP7	ENST00000509061.5	TSL:1	c.191C>A	p.Ser64Tyr	missense	Exon 4 of 15	ENSP00000422626.2	Q4G0J3-1
	LARP7	ENST00000509622.5	TSL:1	n.99+92C>A		intron	N/A	ENSP00000422451.1	D6RBH8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 232194 AF XY: 0.0000238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1418626 Hom.: 0 Cov.: 30 AF XY: 0.00000425 AC XY: 3 AN XY: 705310

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

American (AMR) AF: 0.0000240 AC: 1 AN: 41650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25022

East Asian (EAS) AF: 0.0000527 AC: 2 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

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.50		Loss of disorder (P = 0.0135)
MVP		0.76
MPC		0.33
ClinPred		0.84	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.56
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;