rs201011683

Variant names:

• chr9-131079176-G-A
• rs201011683
• NM_006059.4:c.3805G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-131079176-G-A
• chr9-131079176-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006059.4(LAMC3):​c.3805G>A​(p.Gly1269Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.242
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02594608).

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.3805G>A	p.Gly1269Ser	missense	Exon 23 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.3805G>A	p.Gly1269Ser	missense	Exon 23 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.3805G>A	p.Gly1269Ser	missense	Exon 23 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.3799G>A	p.Gly1267Ser	missense	Exon 23 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000144 AC: 36 AN: 249872 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000302 AC: 442 AN: 1461464 Hom.: 1 Cov.: 32 AF XY: 0.000297 AC XY: 216 AN XY: 726980

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000380 AC: 422 AN: 1111846

Other (OTH) AF: 0.0000828 AC: 5 AN: 60388

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74378

African (AFR) AF: 0.0000482 AC: 2 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.36
DANN	Benign	0.60
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.43	N
PhyloP100		-0.24
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.016
Sift	Benign	0.74	T
Sift4G	Benign	0.75	T
Polyphen		0.0020	B
Vest4		0.029
MVP		0.17
MPC		0.14
ClinPred		0.024	T
GERP RS		-3.0
PromoterAI		-0.042	Neutral
Varity_R		0.026
gMVP		0.26
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201011683; hg19: chr9-133954563; COSMIC: COSV99051842; COSMIC: COSV99051842;