9-131009360-A-G

Variant names:

• chr9-131009360-A-G
• rs201962705
• NM_006059.4:c.146A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006059.4(LAMC3):​c.146A>G​(p.Gln49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,512,498 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 32)
  • Exomes 𝑓: 0.010 (109 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.486
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005258709).
• BP6: Variant 9-131009360-A-G is Benign according to our data. Variant chr9-131009360-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 291085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00633 (963/152046) while in subpopulation NFE AF = 0.0112 (762/67930). AF 95% confidence interval is 0.0106. There are 4 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	NM_006059.4	MANE Select	c.146A>G	p.Gln49Arg	missense	Exon 1 of 28	NP_006050.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	ENST00000361069.9	TSL:2 MANE Select	c.146A>G	p.Gln49Arg	missense	Exon 1 of 28	ENSP00000354360.4

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 963 AN: 151938 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00673 AC: 739 AN: 109748 AF XY: 0.00662

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.000149

Gnomad FIN exome AF: 0.000137

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00714

GnomAD4 exome AF: 0.0104 AC: 14201 AN: 1360452 Hom.: 109 Cov.: 30 AF XY: 0.0103 AC XY: 6927 AN XY: 670886

African (AFR) AF: 0.00140 AC: 39 AN: 27932

American (AMR) AF: 0.00348 AC: 114 AN: 32786

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 260 AN: 24254

East Asian (EAS) AF: 0.00 AC: 0 AN: 32044

South Asian (SAS) AF: 0.00335 AC: 256 AN: 76370

European-Finnish (FIN) AF: 0.000783 AC: 29 AN: 37040

Middle Eastern (MID) AF: 0.00717 AC: 34 AN: 4740

European-Non Finnish (NFE) AF: 0.0122 AC: 13002 AN: 1068634

Other (OTH) AF: 0.00824 AC: 467 AN: 56652

GnomAD4 genome AF: 0.00633 AC: 963 AN: 152046 Hom.: 4 Cov.: 32 AF XY: 0.00572 AC XY: 425 AN XY: 74344

African (AFR) AF: 0.00241 AC: 100 AN: 41516

American (AMR) AF: 0.00229 AC: 35 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.000474 AC: 5 AN: 10544

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0112 AC: 762 AN: 67930

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00812 Hom.: 4

Bravo AF: 0.00632

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00121 AC: 3

ESP6500EA AF: 0.00253 AC: 14

ExAC AF: 0.00269 AC: 174

Asia WGS AF: 0.000868 AC: 3 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Nov 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LAMC3: BS1, BS2

not specified Benign:4

Jun 20, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 14, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 17, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.49
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.47	P
Vest4		0.013
MVP		0.63
MPC		0.16
ClinPred		0.0032	T
GERP RS		2.5
PromoterAI		-0.0098	Neutral
Varity_R		0.23
gMVP		0.22
Mutation Taster		=98/2	polymorphism

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: rs201962705; hg19: chr9-133884747; COSMIC: COSV63091982;