rs2275140

Variant names:

• chr9-131072662-A-G
• rs2275140
• NM_006059.4:c.3244A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-131072662-A-G
• chr9-131072662-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006059.4(LAMC3):​c.3244A>G​(p.Ser1082Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 1,610,304 control chromosomes in the GnomAD database, including 535,209 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1082N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.76 (44804 hom., cov: 31)
  • Exomes 𝑓: 0.82 (490405 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.511
• Publications: 25 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, 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=8.411099E-7).
• BP6: Variant 9-131072662-A-G is Benign according to our data. Variant chr9-131072662-A-G is described in ClinVar as Benign. ClinVar VariationId is 129460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

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.3244A>G	p.Ser1082Gly	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.3244A>G	p.Ser1082Gly	missense	Exon 19 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.3244A>G	p.Ser1082Gly	missense	Exon 19 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.3244A>G	p.Ser1082Gly	missense	Exon 19 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115299 AN: 151892 Hom.: 44801 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.789 AC: 193825 AN: 245808 AF XY: 0.799

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.843

Gnomad OTH exome AF: 0.808

GnomAD4 exome AF: 0.818 AC: 1192532 AN: 1458294 Hom.: 490405 Cov.: 55 AF XY: 0.820 AC XY: 594645 AN XY: 725364

African (AFR) AF: 0.599 AC: 20004 AN: 33402

American (AMR) AF: 0.669 AC: 29725 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 23941 AN: 26070

East Asian (EAS) AF: 0.670 AC: 26558 AN: 39660

South Asian (SAS) AF: 0.812 AC: 69718 AN: 85842

European-Finnish (FIN) AF: 0.861 AC: 45624 AN: 52962

Middle Eastern (MID) AF: 0.843 AC: 3581 AN: 4248

European-Non Finnish (NFE) AF: 0.832 AC: 924921 AN: 1111540

Other (OTH) AF: 0.805 AC: 48460 AN: 60162

GnomAD4 genome AF: 0.759 AC: 115336 AN: 152010 Hom.: 44804 Cov.: 31 AF XY: 0.763 AC XY: 56664 AN XY: 74312

African (AFR) AF: 0.604 AC: 25004 AN: 41430

American (AMR) AF: 0.719 AC: 10977 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3167 AN: 3468

East Asian (EAS) AF: 0.650 AC: 3353 AN: 5158

South Asian (SAS) AF: 0.810 AC: 3907 AN: 4822

European-Finnish (FIN) AF: 0.867 AC: 9170 AN: 10580

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57061 AN: 67962

Other (OTH) AF: 0.788 AC: 1664 AN: 2112

Alfa AF: 0.808 Hom.: 151156

Bravo AF: 0.740

TwinsUK AF: 0.834 AC: 3092

ALSPAC AF: 0.826 AC: 3182

ESP6500AA AF: 0.624 AC: 2748

ESP6500EA AF: 0.841 AC: 7235

ExAC AF: 0.788 AC: 95696

Asia WGS AF: 0.721 AC: 2507 AN: 3476

EpiCase AF: 0.850

EpiControl AF: 0.841

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	Occipital pachygyria and polymicrogyria (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.64
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.51
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.016
Sift	Benign	0.52	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.13
ClinPred		0.0012	T
GERP RS		2.2
Varity_R		0.035
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs2275140; hg19: chr9-133948049; COSMIC: COSV63088882;