rs146018013

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_002291.3(LAMB1):​c.3481C>T​(p.Arg1161Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,614,200 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 5 hom. )

Consequence

LAMB1
NM_002291.3 missense

Scores

8
6
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.31
Variant links:
Genes affected
LAMB1 (HGNC:6486): (laminin subunit beta 1) 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 beta chain isoform laminin, beta 1. The beta 1 chain has 7 structurally distinct domains which it shares with other beta chain isomers. The C-terminal helical region containing domains I and II are separated by domain alpha, domains III and V contain several EGF-like repeats, and domains IV and VI have a globular conformation. Laminin, beta 1 is expressed in most tissues that produce basement membranes, and is one of the 3 chains constituting laminin 1, the first laminin isolated from Engelbreth-Holm-Swarm (EHS) tumor. A sequence in the beta 1 chain that is involved in cell attachment, chemotaxis, and binding to the laminin receptor was identified and shown to have the capacity to inhibit metastasis. [provided by RefSeq, Aug 2011]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.36260283).
BP6
Variant 7-107940269-G-A is Benign according to our data. Variant chr7-107940269-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435718.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000184 (28/152314) while in subpopulation SAS AF= 0.00104 (5/4816). AF 95% confidence interval is 0.000409. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LAMB1NM_002291.3 linkuse as main transcriptc.3481C>T p.Arg1161Cys missense_variant 25/34 ENST00000222399.11
LAMB1XM_047420359.1 linkuse as main transcriptc.3481C>T p.Arg1161Cys missense_variant 25/28

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LAMB1ENST00000222399.11 linkuse as main transcriptc.3481C>T p.Arg1161Cys missense_variant 25/341 NM_002291.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000446
AC:
112
AN:
251396
Hom.:
2
AF XY:
0.000545
AC XY:
74
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00193
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000273
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000244
AC:
356
AN:
1461886
Hom.:
5
Cov.:
32
AF XY:
0.000287
AC XY:
209
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00176
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00187
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000890
Gnomad4 OTH exome
AF:
0.000480
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152314
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000303
Hom.:
0
Bravo
AF:
0.000117
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000519
AC:
63
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 14, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 03, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Benign
-0.077
T
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.37
.;T
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Uncertain
0.36
D
MutationAssessor
Pathogenic
4.1
.;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Uncertain
0.55
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.69
MVP
0.82
MPC
0.55
ClinPred
0.58
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.53
gMVP
0.83

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

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

Other links and lift over

dbSNP: rs146018013; hg19: chr7-107580714; API