Genetic Variant NM_144648.3:c.593C>A (chr7-134148242-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_144648.3(LRGUK):c.593C>A(p.Ala198Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A198V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LRGUK
NM_144648.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

Publications

0 publications found

Variant links:

Genes affected

LRGUK (HGNC:21964): (leucine rich repeats and guanylate kinase domain containing) Predicted to enable guanylate kinase activity. Predicted to be involved in axoneme assembly and spermatogenesis. Predicted to be located in acrosomal vesicle and manchette. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LRGUK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2719188).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144648.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRGUK	NM_144648.3	MANE Select	c.593C>A	p.Ala198Glu	missense	Exon 5 of 20	NP_653249.1	Q96M69
LRGUK	NM_001365700.3		c.593C>A	p.Ala198Glu	missense	Exon 5 of 16	NP_001352629.1	A0A8Q3SI13
LRGUK	NM_001365701.3		c.593C>A	p.Ala198Glu	missense	Exon 5 of 16	NP_001352630.1	A0A2R8YEJ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRGUK	ENST00000285928.3	TSL:1 MANE Select	c.593C>A	p.Ala198Glu	missense	Exon 5 of 20	ENSP00000285928.2	Q96M69
LRGUK	ENST00000695542.2		c.593C>A	p.Ala198Glu	missense	Exon 5 of 16	ENSP00000511999.1	A0A8Q3SI13
LRGUK	ENST00000645682.1		c.593C>A	p.Ala198Glu	missense	Exon 5 of 16	ENSP00000495637.1	A0A2R8YEJ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32618

American (AMR)

AF:

0.00

AC:

AN:

42402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25926

East Asian (EAS)

AF:

0.00

AC:

AN:

39294

South Asian (SAS)

AF:

0.00

AC:

AN:

83262

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103688

Other (OTH)

AF:

0.00

AC:

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.025

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

M_CAP

Benign

0.0091

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

2.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.20

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0020

Polyphen

0.44

Vest4

0.61

MutPred

0.68

Gain of disorder (P = 0.0338)

MVP

0.31

MPC

0.061

ClinPred

0.48

GERP RS

1.8

Varity_R

0.24

gMVP

0.67

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over