rs138481447

Positions:

• chr9-131077231-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006059.4(LAMC3):​c.3674T>C​(p.Val1225Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,992 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.513

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011284053).
• BP6: Variant 9-131077231-T-C is Benign according to our data. Variant chr9-131077231-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430486.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000637 (97/152306) while in subpopulation NFE AF= 0.00115 (78/68024). AF 95% confidence interval is 0.000941. There are 1 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.3674T>C	p.Val1225Ala	missense_variant	22/28	ENST00000361069.9
LAMC3	XM_011518121.2	c.3674T>C	p.Val1225Ala	missense_variant	22/28
LAMC3	XM_006716921.3	c.3674T>C	p.Val1225Ala	missense_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.3674T>C	p.Val1225Ala	missense_variant	22/28	2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152188 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000393

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: 0.00115

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000545 AC: 137 AN: 251156 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135864

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00111 AC: 1626 AN: 1461686 Hom.: 2 Cov.: 31 AF XY: 0.00111 AC XY: 804 AN XY: 727180

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152306 Hom.: 1 Cov.: 31 AF XY: 0.000617 AC XY: 46 AN XY: 74494

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000638

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000763

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	LAMC3: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2022

The c.3674T>C (p.V1225A) alteration is located in exon 22 (coding exon 22) of the LAMC3 gene. This alteration results from a T to C substitution at nucleotide position 3674, causing the valine (V) at amino acid position 1225 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Occipital pachygyria and polymicrogyria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

LAMC3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

The LAMC3 c.3674T>C variant is predicted to result in the amino acid substitution p.Val1225Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-133952618-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.45
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.021
Sift	Benign	1.0	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.29
MPC		0.19
ClinPred		0.0031	T
GERP RS		2.4
Varity_R		0.033
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs138481447; hg19: chr9-133952618;