NM_006059.4:c.368G>T

Variant names:

• chr9-131009582-G-T
• rs140461419
• NM_006059.4:c.368G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006059.4(LAMC3):​c.368G>T​(p.Arg123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,570,672 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.348
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016019285).
• BP6: Variant 9-131009582-G-T is Benign according to our data. Variant chr9-131009582-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	NM_006059.4	MANE Select	c.368G>T	p.Arg123Leu	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.368G>T	p.Arg123Leu	missense	Exon 1 of 28	ENSP00000354360.4
	LAMC3	ENST00000868026.1		c.368G>T	p.Arg123Leu	missense	Exon 1 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.368G>T	p.Arg123Leu	missense	Exon 1 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152118 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00960

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000567 AC: 100 AN: 176284 AF XY: 0.000398

Gnomad AFR exome AF: 0.00906

Gnomad AMR exome AF: 0.000287

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000412

Gnomad OTH exome AF: 0.000211

GnomAD4 exome AF: 0.000250 AC: 355 AN: 1418436 Hom.: 2 Cov.: 33 AF XY: 0.000181 AC XY: 127 AN XY: 701880

African (AFR) AF: 0.00881 AC: 285 AN: 32332

American (AMR) AF: 0.000381 AC: 15 AN: 39320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25324

East Asian (EAS) AF: 0.00 AC: 0 AN: 37158

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48110

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5720

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1091232

Other (OTH) AF: 0.000596 AC: 35 AN: 58774

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152236 Hom.: 1 Cov.: 31 AF XY: 0.00243 AC XY: 181 AN XY: 74436

African (AFR) AF: 0.00958 AC: 398 AN: 41560

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.00314

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00656 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000600 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.35
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.33
Sift	Benign	0.044	D
Sift4G	Benign	0.12	T
Polyphen		0.35	B
Vest4		0.30
MVP		0.58
MPC		0.33
ClinPred		0.044	T
GERP RS		-5.1
PromoterAI		0.0076	Neutral
Varity_R		0.35
gMVP		0.35
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: rs140461419; hg19: chr9-133884969;