rs387907343

Positions:

• chr7-107952144-CTGACCAGTGGCTTT-CATTAGGAAGACACAAGCACATTAGGAAGACACAAGCACTGG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 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. 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107952145-TGACCAGTGGCTTT-ATTAGGAAGACACAAGCACATTAGGAAGACACAAGCACTGG is Pathogenic according to our data. Variant chr7-107952145-TGACCAGTGGCTTT-ATTAGGAAGACACAAGCACATTAGGAAGACACAAGCACTGG is described in ClinVar as [Pathogenic]. Clinvar id is 42014.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB1	NM_002291.3	c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained, missense_variant, conservative_inframe_insertion	23/34	ENST00000222399.11	NP_002282.2
LAMB1	XM_047420359.1	c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained, missense_variant, conservative_inframe_insertion	23/28		XP_047276315.1
LAMB1	XM_047420360.1	c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained, missense_variant, conservative_inframe_insertion	23/25		XP_047276316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB1	ENST00000222399.11	c.3145_3158delAAAGCCACTGGTCAinsCCAGTGCTTGTGTCTTCCTAATGTGCTTGTGTCTTCCTAAT	p.Lys1049_Gln1053delinsProValLeuValSerSerTerCysAlaCysValPheLeuMet	stop_gained, missense_variant, conservative_inframe_insertion	23/34	1	NM_002291.3	ENSP00000222399.6

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cobblestone lissencephaly without muscular or ocular involvement Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 07, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907343; hg19: chr7-107592590;