rs387907343

Variant names:

• chr7-107952145-TGACCAGTGGCTTT-ATTAGGAAGACACAAGCACATTAGGAAGACACAAGCACTGG
• rs387907343
• NM_002291.3:c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_002291.3(LAMB1):​c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT​(p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet) variant causes a stop gained, missense, conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMB1 NM_002291.3 stop_gained, missense, conservative_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.96
• Publications: 1 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, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-107952145-TGACCAGTGGCTTT-ATTAGGAAGACACAAGCACATTAGGAAGACACAAGCACTGG is Pathogenic according to our data. Variant chr7-107952145-TGACCAGTGGCTTT-ATTAGGAAGACACAAGCACATTAGGAAGACACAAGCACTGG is described in ClinVar as Pathogenic. ClinVar VariationId is 42014.Status of the report is no_assertion_criteria_provided, 0 stars.

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.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained missense conservative_inframe_insertion	Exon 23 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.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained missense conservative_inframe_insertion	Exon 23 of 34	ENSP00000222399.6	P07942
	LAMB1	ENST00000943288.1		c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained missense conservative_inframe_insertion	Exon 23 of 34	ENSP00000613347.1
	LAMB1	ENST00000852248.1		c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained missense conservative_inframe_insertion	Exon 23 of 34	ENSP00000522307.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cobblestone lissencephaly without muscular or ocular involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907343;

hg19: chr7-107592590;