rs117621658

Variant names:

• chr9-131069872-C-T
• rs117621658
• NM_006059.4:c.3069+22C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006059.4(LAMC3):​c.3069+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,565,466 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (10 hom.)
• Consequence: LAMC3 NM_006059.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00600
• Publications: 1 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-131069872-C-T is Benign according to our data. Variant chr9-131069872-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 435731.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.3069+22C>T		intron	N/A	NP_006050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	ENST00000361069.9	TSL:2 MANE Select	c.3069+22C>T		intron	N/A	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.3069+22C>T		intron	N/A	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.3069+22C>T		intron	N/A	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00296 AC: 524 AN: 177020 AF XY: 0.00299

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00898

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00235

Gnomad NFE exome AF: 0.00445

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00409 AC: 5777 AN: 1413122 Hom.: 10 Cov.: 31 AF XY: 0.00401 AC XY: 2802 AN XY: 698794

African (AFR) AF: 0.000523 AC: 17 AN: 32496

American (AMR) AF: 0.00113 AC: 43 AN: 38050

Ashkenazi Jewish (ASJ) AF: 0.00981 AC: 249 AN: 25378

East Asian (EAS) AF: 0.00 AC: 0 AN: 37440

South Asian (SAS) AF: 0.00129 AC: 104 AN: 80552

European-Finnish (FIN) AF: 0.00184 AC: 91 AN: 49472

Middle Eastern (MID) AF: 0.000372 AC: 2 AN: 5382

European-Non Finnish (NFE) AF: 0.00459 AC: 4979 AN: 1085858

Other (OTH) AF: 0.00499 AC: 292 AN: 58494

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.00273 AC XY: 203 AN XY: 74494

African (AFR) AF: 0.000914 AC: 38 AN: 41592

American (AMR) AF: 0.00105 AC: 16 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

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

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00484 AC: 329 AN: 68036

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00426 Hom.: 0

Bravo AF: 0.00267

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		-0.0060
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs117621658;

hg19: chr9-133945259;