rs36030184

Variant names:

• chr9-131061103-A-G
• rs36030184
• NM_006059.4:c.2227A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006059.4(LAMC3):​c.2227A>G​(p.Asn743Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,042 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 2.28
• Publications: 3 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), G2P, Ambry Genetics, Illumina, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014074862).
• BP6: Variant 9-131061103-A-G is Benign according to our data. Variant chr9-131061103-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372404.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	NM_006059.4	MANE Select	c.2227A>G	p.Asn743Asp	missense	Exon 13 of 28	NP_006050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	ENST00000361069.9	TSL:2 MANE Select	c.2227A>G	p.Asn743Asp	missense	Exon 13 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.2227A>G	p.Asn743Asp	missense	Exon 13 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.2227A>G	p.Asn743Asp	missense	Exon 13 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000342 AC: 86 AN: 251248 AF XY: 0.000353

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000226 AC: 330 AN: 1461746 Hom.: 2 Cov.: 36 AF XY: 0.000224 AC XY: 163 AN XY: 727186

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 136 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1112008

Other (OTH) AF: 0.000646 AC: 39 AN: 60394

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74480

African (AFR) AF: 0.00197 AC: 82 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000756

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	2	-	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	LAMC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Benign	0.66
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.32	N
PhyloP100		2.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.14
Sift	Benign	0.83	T
Sift4G	Benign	0.63	T
Polyphen		0.48	P
Vest4		0.20
MVP		0.74
MPC		0.41
ClinPred		0.075	T
GERP RS		3.7
Varity_R		0.27
gMVP		0.36
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs36030184; hg19: chr9-133936490; COSMIC: COSV105266520;