rs533170505

Variant names:

• chr9-131009176-G-A
• rs533170505
• NM_006059.4:c.-39G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006059.4(LAMC3):​c.-39G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,170,294 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: LAMC3 NM_006059.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.56
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-131009176-G-A is Benign according to our data. Variant chr9-131009176-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 381809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00404 (613/151826) while in subpopulation AFR AF = 0.014 (583/41518). AF 95% confidence interval is 0.0131. There are 5 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.-39G>A		5_prime_UTR	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.-39G>A		5_prime_UTR	Exon 1 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000955223.1		c.-39G>A		5_prime_UTR	Exon 1 of 27	ENSP00000625282.1
	LAMC3	ENST00000868026.1		c.-39G>A		upstream_gene	N/A	ENSP00000538085.1

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 609 AN: 151718 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00 AC: 0 AN: 326 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000322 AC: 328 AN: 1018468 Hom.: 3 Cov.: 29 AF XY: 0.000317 AC XY: 152 AN XY: 480026

African (AFR) AF: 0.0130 AC: 266 AN: 20518

American (AMR) AF: 0.00273 AC: 17 AN: 6236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11276

East Asian (EAS) AF: 0.00 AC: 0 AN: 19244

South Asian (SAS) AF: 0.000107 AC: 2 AN: 18726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18238

Middle Eastern (MID) AF: 0.000390 AC: 1 AN: 2564

European-Non Finnish (NFE) AF: 0.00000453 AC: 4 AN: 882650

Other (OTH) AF: 0.000974 AC: 38 AN: 39016

GnomAD4 genome AF: 0.00404 AC: 613 AN: 151826 Hom.: 5 Cov.: 32 AF XY: 0.00396 AC XY: 294 AN XY: 74228

African (AFR) AF: 0.0140 AC: 583 AN: 41518

American (AMR) AF: 0.00138 AC: 21 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67896

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00435

Asia WGS AF: 0.000589 AC: 2 AN: 3410

ClinVar

ClinVar submissions as Germline

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	-0.76
CADD	Benign	6.6
DANN	Benign	0.78
PhyloP100		1.6
PromoterAI		-0.012	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs533170505; hg19: chr9-133884563;