Genetic Variant NM_003667.4:c.1304C>T (chr12-71578827-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_003667.4(LGR5):c.1304C>T(p.Ser435Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,609,742 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

LGR5
NM_003667.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.61

Publications

7 publications found

Variant links:

Genes affected

LGR5 (HGNC:4504): (leucine rich repeat containing G protein-coupled receptor 5) The protein encoded by this gene is a leucine-rich repeat-containing receptor (LGR) and member of the G protein-coupled, 7-transmembrane receptor (GPCR) superfamily. The encoded protein is a receptor for R-spondins and is involved in the canonical Wnt signaling pathway. This protein plays a role in the formation and maintenance of adult intestinal stem cells during postembryonic development. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

LGR5 links:

LOC124902963 (HGNC:):

LOC124902963 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011430353).

BP6

Variant 12-71578827-C-T is Benign according to our data. Variant chr12-71578827-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 722963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGR5	NM_003667.4 link	c.1304C>T	p.Ser435Leu	missense_variant	Exon 15 of 18	ENST00000266674.10	NP_003658.1	O75473-1A0A0A8K8C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGR5	ENST00000266674.10 link	c.1304C>T	p.Ser435Leu	missense_variant	Exon 15 of 18	1	NM_003667.4	ENSP00000266674.4		O75473-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

284

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000535

AC:

133

AN:

248818

AF XY:

0.000424

show subpopulations

Gnomad AFR exome

AF:

0.00719

Gnomad AMR exome

AF:

0.000327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000257

AC:

375

AN:

1457522

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

169

AN XY:

724984

show subpopulations

African (AFR)

AF:

0.00723

AC:

241

AN:

33328

American (AMR)

AF:

0.000384

AC:

AN:

44268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

85432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000685

AC:

AN:

1109646

Other (OTH)

AF:

0.000548

AC:

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.00187

AC:

284

AN:

152220

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00616

AC:

256

AN:

41542

American (AMR)

AF:

0.000589

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000744

Hom.:

Bravo

AF:

0.00215

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.95

L;.;.

PhyloP100

2.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

0.89

P;.;P

Vest4

0.68

MVP

0.68

MPC

0.064

ClinPred

0.032

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.53

Mutation Taster

=70/30

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over