NM_002291.3:c.*85A>G

Variant names:

• chr7-107923866-T-C
• rs78245660
• NM_002291.3:c.*85A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002291.3(LAMB1):​c.*85A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,177,322 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (11 hom.)
• Consequence: LAMB1 NM_002291.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.385
• Publications: 2 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]

DLD (HGNC:2898): (dihydrolipoamide dehydrogenase) This gene encodes a member of the class-I pyridine nucleotide-disulfide oxidoreductase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In homodimeric form, the encoded protein functions as a dehydrogenase and is found in several multi-enzyme complexes that regulate energy metabolism. However, as a monomer, this protein can function as a protease. Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

DLD Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Myriad Women’s Health, G2P, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-107923866-T-C is Benign according to our data. Variant chr7-107923866-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1208455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00864 (1316/152356) while in subpopulation AFR AF = 0.0301 (1250/41590). AF 95% confidence interval is 0.0287. There are 22 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMB1	NM_002291.3	MANE Select	c.*85A>G		3_prime_UTR	Exon 34 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.*85A>G		3_prime_UTR	Exon 34 of 34	ENSP00000222399.6	P07942
	LAMB1	ENST00000943288.1		c.*85A>G		3_prime_UTR	Exon 34 of 34	ENSP00000613347.1
	LAMB1	ENST00000852248.1		c.*85A>G		3_prime_UTR	Exon 34 of 34	ENSP00000522307.1

Frequencies

GnomAD3 genomes AF: 0.00864 AC: 1316 AN: 152238 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.000783 AC: 803 AN: 1024966 Hom.: 11 Cov.: 13 AF XY: 0.000721 AC XY: 379 AN XY: 525582

African (AFR) AF: 0.0277 AC: 580 AN: 20938

American (AMR) AF: 0.00203 AC: 55 AN: 27044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19444

East Asian (EAS) AF: 0.00 AC: 0 AN: 35276

South Asian (SAS) AF: 0.0000749 AC: 5 AN: 66794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46974

Middle Eastern (MID) AF: 0.000422 AC: 2 AN: 4742

European-Non Finnish (NFE) AF: 0.0000817 AC: 62 AN: 758522

Other (OTH) AF: 0.00219 AC: 99 AN: 45232

GnomAD4 genome AF: 0.00864 AC: 1316 AN: 152356 Hom.: 22 Cov.: 32 AF XY: 0.00825 AC XY: 615 AN XY: 74508

African (AFR) AF: 0.0301 AC: 1250 AN: 41590

American (AMR) AF: 0.00288 AC: 44 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00376 Hom.: 4

Bravo AF: 0.0103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		0.39
Mutation Taster		=100/0	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: rs78245660; hg19: chr7-107564311;