Genetic Variant LRRC3B:p.Asp191Glu (chr3-26710245-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052953.4(LRRC3B):c.573C>G(p.Asp191Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D191D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LRRC3B
NM_052953.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.496

Publications

2 publications found

Variant links:

Genes affected

LRRC3B (HGNC:28105): (leucine rich repeat containing 3B) The protein encoded by this gene is a tumor suppressor, with lowered expression levels found in gastric, renal, colorectal, lung, and breast cancer tissues. The promoter of this gene is frequently hypermethylated in these cancer tissues, although the hypermethylation does not appear to be the cause of the reduced expression of this gene. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2015]

LRRC3B links:

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ACMG classification

Classification was made for transcript

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=0.1731647).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC3B	NM_052953.4	MANE Select	c.573C>G	p.Asp191Glu	missense	Exon 2 of 2	NP_443185.1	Q96PB8
LRRC3B	NM_001317808.2		c.573C>G	p.Asp191Glu	missense	Exon 2 of 2	NP_001304737.1	Q96PB8
LRRC3B	NM_001317809.2		c.573C>G	p.Asp191Glu	missense	Exon 2 of 2	NP_001304738.1	Q96PB8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC3B	ENST00000396641.7	TSL:1 MANE Select	c.573C>G	p.Asp191Glu	missense	Exon 2 of 2	ENSP00000379880.2	Q96PB8
LRRC3B	ENST00000417744.5	TSL:1	c.573C>G	p.Asp191Glu	missense	Exon 3 of 3	ENSP00000406370.1	Q96PB8
LRRC3B	ENST00000456208.2	TSL:1	c.573C>G	p.Asp191Glu	missense	Exon 3 of 3	ENSP00000394940.2	Q96PB8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249524

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727020

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111844

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.15

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.026

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.81

M_CAP

Benign

0.020

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.40

PhyloP100

-0.50

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.65

REVEL

Benign

0.19

Sift

Benign

0.66

Sift4G

Benign

0.17

Polyphen

0.74

Vest4

0.53

MutPred

0.38

Gain of sheet (P = 0.0827)

MVP

0.28

MPC

0.99

ClinPred

0.093

GERP RS

-6.4

Varity_R

0.092

gMVP

0.78

Mutation Taster

=56/44

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over