NM_006059.4:c.3379G>A

Variant names:

• chr9-131072797-G-A
• rs140955110
• NM_006059.4:c.3379G>A

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.3379G>A​(p.Glu1127Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,613,266 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (35 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 1.47
• Publications: 9 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=0.0077517927).
• BP6: Variant 9-131072797-G-A is Benign according to our data. Variant chr9-131072797-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194959.
• BS2: High Homozygotes in GnomAdExome4 at 35 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.3379G>A	p.Glu1127Lys	missense	Exon 19 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.3379G>A	p.Glu1127Lys	missense	Exon 19 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.3379G>A	p.Glu1127Lys	missense	Exon 19 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.3379G>A	p.Glu1127Lys	missense	Exon 19 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00347 AC: 862 AN: 248258 AF XY: 0.00372

Gnomad AFR exome AF: 0.000689

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00421

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000805

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00526 AC: 7679 AN: 1460954 Hom.: 35 Cov.: 36 AF XY: 0.00537 AC XY: 3901 AN XY: 726670

African (AFR) AF: 0.000717 AC: 24 AN: 33470

American (AMR) AF: 0.00226 AC: 101 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00527 AC: 453 AN: 85936

European-Finnish (FIN) AF: 0.000825 AC: 44 AN: 53316

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.00593 AC: 6596 AN: 1111740

Other (OTH) AF: 0.00568 AC: 343 AN: 60362

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74480

African (AFR) AF: 0.00111 AC: 46 AN: 41568

American (AMR) AF: 0.00379 AC: 58 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

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

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00543 AC: 369 AN: 68014

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00443 Hom.: 4

Bravo AF: 0.00318

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00339 AC: 412

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00619

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	LAMC3-related disorder (1)
-	-	1	Left ventricular noncompaction (1)
-	-	1	Occipital pachygyria and polymicrogyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.025
Sift	Benign	0.12	T
Sift4G	Benign	0.46	T
Polyphen		0.049	B
Vest4		0.39
MVP		0.48
MPC		0.17
ClinPred		0.0073	T
GERP RS		4.0
Varity_R		0.083
gMVP		0.22
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140955110; hg19: chr9-133948184;