rs113443891

chr9-131057055-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006059.4(LAMC3):c.2066C>T(p.Pro689Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,132 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P689P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 0.919

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0112422705).
• BP6: Variant 9-131057055-C-T is Benign according to our data. Variant chr9-131057055-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194074.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr9-131057055-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00112 (171/152318) while in subpopulation AFR AF= 0.0032 (133/41570). AF 95% confidence interval is 0.00276. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMC3	NM_006059.4	c.2066C>T	p.Pro689Leu	missense_variant	12/28	ENST00000361069.9
LAMC3	XM_011518121.2	c.2066C>T	p.Pro689Leu	missense_variant	12/28
LAMC3	XM_006716921.3	c.2066C>T	p.Pro689Leu	missense_variant	12/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMC3	ENST00000361069.9	c.2066C>T	p.Pro689Leu	missense_variant	12/28	2	NM_006059.4	P1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000581 AC: 146 AN: 251350 Hom.: 1 AF XY: 0.000559 AC XY: 76 AN XY: 135866

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1461814 Hom.: 2 Cov.: 33 AF XY: 0.000296 AC XY: 215 AN XY: 727208

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74462

Gnomad4 AFR AF: 0.00320

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000493 Hom.: 0

Bravo AF: 0.00119

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 30924900) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LAMC3: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2022	Variant summary: LAMC3 c.2066C>T (p.Pro689Leu) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 282742 control chromosomes, including 1 homozygote (gnomAD). To our knowledge, no occurrence of c.2066C>T in individuals affected with Occipital Pachygyria And Polymicrogyria and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 13, 2017	- -

Occipital pachygyria and polymicrogyria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

LAMC3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.14
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.52	P
Vest4		0.30
MVP		0.80
MPC		0.33
ClinPred		0.087	T
GERP RS		0.75
Varity_R		0.20
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs113443891; hg19: chr9-133932442; COSMIC: COSV63093334;