chr7-107986311-G-C

Variant names:

• chr7-107986311-G-C
• rs140146478
• NM_002291.3:c.476C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002291.3(LAMB1):​c.476C>G​(p.Thr159Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,611,192 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: LAMB1 NM_002291.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 6.83
• 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 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016529769).
• BP6: Variant 7-107986311-G-C is Benign according to our data. Variant chr7-107986311-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252602.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00226 (344/152248) while in subpopulation NFE AF = 0.00306 (208/68016). AF 95% confidence interval is 0.00272. There are 1 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB1	NM_002291.3	MANE Select	c.476C>G	p.Thr159Ser	missense	Exon 6 of 34	NP_002282.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB1	ENST00000222399.11	TSL:1 MANE Select	c.476C>G	p.Thr159Ser	missense	Exon 6 of 34	ENSP00000222399.6
	LAMB1	ENST00000393560.5	TSL:1	c.476C>G	p.Thr159Ser	missense	Exon 6 of 19	ENSP00000377190.1
	LAMB1	ENST00000677793.1		c.476C>G	p.Thr159Ser	missense	Exon 6 of 32	ENSP00000504020.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152130 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00217 AC: 545 AN: 251018 AF XY: 0.00212

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00637

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00278 AC: 4061 AN: 1458944 Hom.: 9 Cov.: 31 AF XY: 0.00278 AC XY: 2014 AN XY: 725112

African (AFR) AF: 0.000239 AC: 8 AN: 33434

American (AMR) AF: 0.00226 AC: 101 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00640 AC: 167 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86054

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53404

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00315 AC: 3495 AN: 1109636

Other (OTH) AF: 0.00244 AC: 147 AN: 60264

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152248 Hom.: 1 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74440

African (AFR) AF: 0.000602 AC: 25 AN: 41544

American (AMR) AF: 0.00301 AC: 46 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00280 Hom.: 1

Bravo AF: 0.00229

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00194 AC: 236

EpiCase AF: 0.00360

EpiControl AF: 0.00397

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	-	not specified (2)
-	-	1	LAMB1-related disorder (1)
1	-	-	Multiple sclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.39
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.27	B
Vest4		0.24
MutPred		0.76		Gain of disorder (P = 0.055)
MVP		0.73
MPC		0.11
ClinPred		0.036	T
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.14
gMVP		0.58
Mutation Taster		=98/2	polymorphism

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: rs140146478; hg19: chr7-107626756; COSMIC: COSV99033440;