rs146045042

Variant names:

• chr7-107935420-C-T
• rs146045042
• NM_002291.3:c.4183G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_002291.3(LAMB1):​c.4183G>A​(p.Glu1395Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,470,472 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: LAMB1 NM_002291.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.56
• Publications: 4 publications found

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]

LAMB1 Gene-Disease associations (from GenCC):

• cobblestone lissencephaly without muscular or ocular involvement

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32476115).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002291.3. 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
	LAMB1	NM_002291.3	MANE Select	c.4183G>A	p.Glu1395Lys	missense	Exon 27 of 34	NP_002282.2	P07942

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB1	ENST00000222399.11	TSL:1 MANE Select	c.4183G>A	p.Glu1395Lys	missense	Exon 27 of 34	ENSP00000222399.6	P07942
	LAMB1	ENST00000943288.1		c.4183G>A	p.Glu1395Lys	missense	Exon 27 of 34	ENSP00000613347.1
	LAMB1	ENST00000852248.1		c.4183G>A	p.Glu1395Lys	missense	Exon 27 of 34	ENSP00000522307.1

Frequencies

GnomAD3 genomes AF: 0.000218 AC: 28 AN: 128282 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000403

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000959 AC: 24 AN: 250178 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000306 AC: 411 AN: 1342138 Hom.: 1 Cov.: 35 AF XY: 0.000279 AC XY: 186 AN XY: 666782

African (AFR) AF: 0.00 AC: 0 AN: 29424

American (AMR) AF: 0.0000734 AC: 3 AN: 40858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21688

East Asian (EAS) AF: 0.00 AC: 0 AN: 27696

South Asian (SAS) AF: 0.00 AC: 0 AN: 84762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42912

Middle Eastern (MID) AF: 0.000208 AC: 1 AN: 4802

European-Non Finnish (NFE) AF: 0.000370 AC: 384 AN: 1037686

Other (OTH) AF: 0.000440 AC: 23 AN: 52310

GnomAD4 genome AF: 0.000218 AC: 28 AN: 128334 Hom.: 0 Cov.: 29 AF XY: 0.000133 AC XY: 8 AN XY: 60314

African (AFR) AF: 0.0000611 AC: 2 AN: 32758

American (AMR) AF: 0.00 AC: 0 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 4028

South Asian (SAS) AF: 0.00 AC: 0 AN: 3842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.000403 AC: 26 AN: 64520

Other (OTH) AF: 0.00 AC: 0 AN: 1754

Alfa AF: 0.000398 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cobblestone lissencephaly without muscular or ocular involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.15
Sift	Benign	0.053	T
Sift4G	Benign	0.16	T
Polyphen		0.55	P
Vest4		0.69
MVP		0.32
MPC		0.12
ClinPred		0.094	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.49
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs146045042; hg19: chr7-107575865; COSMIC: COSV55969356; COSMIC: COSV55969356;