rs79073119

Variant names:

• chr7-107924091-TGG-T
• rs79073119
• NM_002291.3:c.5225-6_5225-5delCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002291.3(LAMB1):​c.5225-6_5225-5delCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,367,722 control chromosomes in the GnomAD database, including 53 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 30)
  • Exomes 𝑓: 0.0057 (30 hom.)
• Consequence: LAMB1 NM_002291.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.864
• 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 -16 ACMG points.

• BP6: Variant 7-107924091-TGG-T is Benign according to our data. Variant chr7-107924091-TGG-T is described in ClinVar as Benign. ClinVar VariationId is 506354.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 = 0.0121 (1469/121136) while in subpopulation AFR AF = 0.0424 (1331/31424). AF 95% confidence interval is 0.0405. There are 23 homozygotes in GnomAd4. There are 683 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.5225-6_5225-5delCC		splice_region intron	N/A	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.5225-6_5225-5delCC		splice_region intron	N/A	ENSP00000222399.6	P07942
	LAMB1	ENST00000943288.1		c.5297-6_5297-5delCC		splice_region intron	N/A	ENSP00000613347.1
	LAMB1	ENST00000852248.1		c.5225-6_5225-5delCC		splice_region intron	N/A	ENSP00000522307.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1459 AN: 121072 Hom.: 23 Cov.: 30

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.000349

Gnomad EAS AF: 0.00565

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.000121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000815

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.0168 AC: 1793 AN: 106604 AF XY: 0.0163

Gnomad AFR exome AF: 0.0616

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0225

Gnomad FIN exome AF: 0.00695

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00573 AC: 7137 AN: 1246586 Hom.: 30 AF XY: 0.00567 AC XY: 3504 AN XY: 617520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0396 AC: 1006 AN: 25376

American (AMR) AF: 0.00913 AC: 234 AN: 25640

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 87 AN: 18968

East Asian (EAS) AF: 0.00861 AC: 261 AN: 30298

South Asian (SAS) AF: 0.00534 AC: 355 AN: 66512

European-Finnish (FIN) AF: 0.00321 AC: 143 AN: 44612

Middle Eastern (MID) AF: 0.00364 AC: 18 AN: 4944

European-Non Finnish (NFE) AF: 0.00477 AC: 4674 AN: 979434

Other (OTH) AF: 0.00707 AC: 359 AN: 50802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0121 AC: 1469 AN: 121136 Hom.: 23 Cov.: 30 AF XY: 0.0116 AC XY: 683 AN XY: 58966

African (AFR) AF: 0.0424 AC: 1331 AN: 31424

American (AMR) AF: 0.00418 AC: 51 AN: 12204

Ashkenazi Jewish (ASJ) AF: 0.000349 AC: 1 AN: 2864

East Asian (EAS) AF: 0.00565 AC: 20 AN: 3538

South Asian (SAS) AF: 0.00158 AC: 6 AN: 3800

European-Finnish (FIN) AF: 0.000121 AC: 1 AN: 8296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000815 AC: 46 AN: 56422

Other (OTH) AF: 0.00762 AC: 13 AN: 1706

Alfa AF: 0.00527 Hom.: 6

Asia WGS AF: 0.0170 AC: 59 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.86
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: rs79073119; hg19: chr7-107564536; COSMIC: COSV105030924; COSMIC: COSV105030924;