rs2275135

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006059.4(LAMC3):c.558C>T(p.Arg186Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,358 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 17 hom. )

Consequence

LAMC3
NM_006059.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.250

Publications

4 publications found

Variant links:

Genes affected

LAMC3 (HGNC:6494): (laminin subunit gamma 3) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 3. The gamma 3 chain is most similar to the gamma 1 chain, and contains all the 6 domains expected of the gamma chain. It is a component of laminin 12. The gamma 3 chain is broadly expressed in skin, heart, lung, and the reproductive tracts. In skin, it is seen within the basement membrane of the dermal-epidermal junction at points of nerve penetration. Gamma 3 is also a prominent element of the apical surface of ciliated epithelial cells of lung, oviduct, epididymis, ductus deferens, and seminiferous tubules. The distribution of gamma 3-containing laminins along ciliated epithelial surfaces suggests that the apical laminins are important in the morphogenesis and structural stability of the ciliated processes of these cells. [provided by RefSeq, Aug 2011]

LAMC3 Gene-Disease associations (from GenCC):

occipital pachygyria and polymicrogyria
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, Illumina
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LAMC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 9-131026469-C-T is Benign according to our data. Variant chr9-131026469-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.25 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00217 (3173/1460984) while in subpopulation EAS AF = 0.0143 (569/39692). AF 95% confidence interval is 0.0134. There are 17 homozygotes in GnomAdExome4. There are 1601 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LAMC3	NM_006059.4 link	c.558C>T	p.Arg186Arg	synonymous_variant	Exon 2 of 28	ENST00000361069.9	NP_006050.3
LAMC3	XM_011518121.2 link	c.558C>T	p.Arg186Arg	synonymous_variant	Exon 2 of 28		XP_011516423.1
LAMC3	XM_006716921.3 link	c.558C>T	p.Arg186Arg	synonymous_variant	Exon 2 of 23		XP_006716984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC3	ENST00000361069.9 link	c.558C>T	p.Arg186Arg	synonymous_variant	Exon 2 of 28	2	NM_006059.4	ENSP00000354360.4

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00481

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00164

AC:

410

AN:

249766

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00248

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00217

AC:

3173

AN:

1460984

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1601

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33462

American (AMR)

AF:

0.000224

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.0143

AC:

569

AN:

39692

South Asian (SAS)

AF:

0.00239

AC:

206

AN:

86228

European-Finnish (FIN)

AF:

0.00155

AC:

AN:

52958

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00198

AC:

2200

AN:

1111730

Other (OTH)

AF:

0.00162

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

203

406

608

811

1014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00119

AC:

182

AN:

152374

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41586

American (AMR)

AF:

0.000457

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00482

AC:

AN:

5188

South Asian (SAS)

AF:

0.00269

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

68032

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00164

Hom.:

Bravo

AF:

0.00107

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 10, 2020

GeneDx

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

- -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LAMC3: BP4, BP7, BS1, BS2 -

not specified

Benign:1

Feb 27, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Occipital pachygyria and polymicrogyria

Benign:1

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.8

(source)

DANN

Benign

0.88

PhyloP100

-0.25

Mutation Taster

=100/0

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