NM_002291.3:c.1945G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002291.3(LAMB1):c.1945G>A(p.Asp649Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000253 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D649G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

LAMB1
NM_002291.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.77

Publications

0 publications found

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]

LAMB1 Gene-Disease associations (from GenCC):

cobblestone lissencephaly without muscular or ocular involvement
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia, Genomics England PanelApp, G2P

LAMB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010612786).

BP6

Variant 7-107961589-C-T is Benign according to our data. Variant chr7-107961589-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435721.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00138 (210/152240) while in subpopulation AFR AF = 0.00457 (190/41532). AF 95% confidence interval is 0.00404. There are 3 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB1	NM_002291.3 link	c.1945G>A	p.Asp649Asn	missense_variant	Exon 16 of 34	ENST00000222399.11	NP_002282.2	P07942Q8TAS6
LAMB1	XM_047420359.1 link	c.1945G>A	p.Asp649Asn	missense_variant	Exon 16 of 28		XP_047276315.1
LAMB1	XM_047420360.1 link	c.1945G>A	p.Asp649Asn	missense_variant	Exon 16 of 25		XP_047276316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB1	ENST00000222399.11 link	c.1945G>A	p.Asp649Asn	missense_variant	Exon 16 of 34	1	NM_002291.3	ENSP00000222399.6		P07942

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000370

AC:

AN:

251438

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00373

AC:

125

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111954

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152240

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00457

AC:

190

AN:

41532

American (AMR)

AF:

0.000850

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000476

Hom.:

Bravo

AF:

0.00139

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000395

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 07, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 01, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

.;T;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

.;M;.

PhyloP100

4.8

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.82

N;N;N

REVEL

Benign

0.090

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

1.0

D;B;P

Vest4

0.69

MVP

0.59

MPC

0.21

ClinPred

0.029

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.033

gMVP

0.49

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over