chr9-131085653-C-T

Position:

chr9-131085653-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_006059.4(LAMC3):c.4160C>T(p.Ala1387Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. A1387A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

LAMC3
NM_006059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.97

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0075733364).

BP6

Variant 9-131085653-C-T is Benign according to our data. Variant chr9-131085653-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211367.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.002 (304/152338) while in subpopulation AFR AF= 0.00664 (276/41578). AF 95% confidence interval is 0.00599. There are 1 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMC3	NM_006059.4 linkuse as main transcript	c.4160C>T	p.Ala1387Val	missense_variant	25/28	ENST00000361069.9	NP_006050.3
LAMC3	XM_011518121.2 linkuse as main transcript	c.4178C>T	p.Ala1393Val	missense_variant	25/28		XP_011516423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LAMC3	ENST00000361069.9 linkuse as main transcript	c.4160C>T	p.Ala1387Val	missense_variant	25/28	2	NM_006059.4	ENSP00000354360	P1
LAMC3	ENST00000355452.5 linkuse as main transcript	c.206C>T	p.Ala69Val	missense_variant	3/6	1		ENSP00000347627
LAMC3	ENST00000678758.1 linkuse as main transcript	c.320C>T	p.Ala107Val	missense_variant	3/6			ENSP00000503612
LAMC3	ENST00000678544.1 linkuse as main transcript	n.1733C>T		non_coding_transcript_exon_variant	3/6

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000309

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000577

AC:

145

AN:

251268

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00579

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000586

AC:

856

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000572

AC XY:

416

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00663

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000504

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152338

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00664

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000401

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000568

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 18, 2015

- -

Occipital pachygyria and polymicrogyria

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 12, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

LAMC3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2020

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

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

0.036

Eigen_PC

Benign

-0.016

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.79

M_CAP

Benign

0.050

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.23

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.41

MVP

0.65

MPC

0.47

ClinPred

0.072

GERP RS

5.1

Varity_R

0.22

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over