9-131009289-C-T

Variant names:

• chr9-131009289-C-T
• rs13286358
• NM_006059.4:c.75C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006059.4(LAMC3):​c.75C>T​(p.Cys25Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,417,940 control chromosomes in the GnomAD database, including 3,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (1317 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2104 hom.)
• Consequence: LAMC3 NM_006059.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.08
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 9-131009289-C-T is Benign according to our data. Variant chr9-131009289-C-T is described in ClinVar as Benign. ClinVar VariationId is 129472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.75C>T	p.Cys25Cys	synonymous	Exon 1 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.75C>T	p.Cys25Cys	synonymous	Exon 1 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.75C>T	p.Cys25Cys	synonymous	Exon 1 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.75C>T	p.Cys25Cys	synonymous	Exon 1 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.0955 AC: 14470 AN: 151508 Hom.: 1312 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0629

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0577

Gnomad NFE AF: 0.0470

Gnomad OTH AF: 0.0761

GnomAD2 exomes AF: 0.0335 AC: 1602 AN: 47810 AF XY: 0.0300

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0485 AC: 61406 AN: 1266322 Hom.: 2104 Cov.: 30 AF XY: 0.0469 AC XY: 29150 AN XY: 621450

African (AFR) AF: 0.245 AC: 6084 AN: 24828

American (AMR) AF: 0.0411 AC: 756 AN: 18414

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 642 AN: 20042

East Asian (EAS) AF: 0.00 AC: 0 AN: 26870

South Asian (SAS) AF: 0.00688 AC: 442 AN: 64284

European-Finnish (FIN) AF: 0.0295 AC: 948 AN: 32132

Middle Eastern (MID) AF: 0.0497 AC: 183 AN: 3682

European-Non Finnish (NFE) AF: 0.0483 AC: 49449 AN: 1024138

Other (OTH) AF: 0.0559 AC: 2902 AN: 51932

GnomAD4 genome AF: 0.0956 AC: 14500 AN: 151618 Hom.: 1317 Cov.: 32 AF XY: 0.0920 AC XY: 6818 AN XY: 74110

African (AFR) AF: 0.236 AC: 9767 AN: 41448

American (AMR) AF: 0.0627 AC: 955 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5162

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4832

European-Finnish (FIN) AF: 0.0247 AC: 256 AN: 10368

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0470 AC: 3185 AN: 67812

Other (OTH) AF: 0.0753 AC: 158 AN: 2098

Alfa AF: 0.0596 Hom.: 400

Bravo AF: 0.104

Asia WGS AF: 0.0180 AC: 61 AN: 3436

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Uncertain	0.98
PhyloP100		1.1
PromoterAI		-0.0090	Neutral
Mutation Taster		=99/1	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: rs13286358; hg19: chr9-133884676;