rs4727695

Variant names:

• chr7-107973558-A-G
• rs4727695
• NM_002291.3:c.1483-487T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002291.3(LAMB1):​c.1483-487T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.084 in 152,292 control chromosomes in the GnomAD database, including 598 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.084 (598 hom., cov: 32)
• Consequence: LAMB1 NM_002291.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• Publications: 12 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 Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB1	NM_002291.3	c.1483-487T>C		intron_variant	Intron 12 of 33	ENST00000222399.11	NP_002282.2
LAMB1	XM_047420359.1	c.1483-487T>C		intron_variant	Intron 12 of 27		XP_047276315.1
LAMB1	XM_047420360.1	c.1483-487T>C		intron_variant	Intron 12 of 24		XP_047276316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMB1	ENST00000222399.11	c.1483-487T>C		intron_variant	Intron 12 of 33	1	NM_002291.3	ENSP00000222399.6

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12804 AN: 152174 Hom.: 602 Cov.: 32

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0602

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0912

Gnomad OTH AF: 0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0840 AC: 12799 AN: 152292 Hom.: 598 Cov.: 32 AF XY: 0.0853 AC XY: 6354 AN XY: 74456

African (AFR) AF: 0.0488 AC: 2029 AN: 41560

American (AMR) AF: 0.152 AC: 2329 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3470

East Asian (EAS) AF: 0.0599 AC: 311 AN: 5188

South Asian (SAS) AF: 0.104 AC: 503 AN: 4830

European-Finnish (FIN) AF: 0.0573 AC: 608 AN: 10612

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0912 AC: 6200 AN: 68018

Other (OTH) AF: 0.110 AC: 232 AN: 2116

Alfa AF: 0.0905 Hom.: 1372

Bravo AF: 0.0893

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.3
DANN	Benign	0.55
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4727695; hg19: chr7-107614003;