7-107924091-TGG-T

Position:

• chr7-107924091-TGG-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002291.3(LAMB1):​c.5225-6_5225-5del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.864

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 506354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107924091-TGG-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMB1	NM_002291.3	c.5225-6_5225-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000222399.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMB1	ENST00000222399.11	c.5225-6_5225-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002291.3	P1

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

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

Gnomad4 AFR exome AF: 0.0396

Gnomad4 AMR exome AF: 0.00913

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.00861

Gnomad4 SAS exome AF: 0.00534

Gnomad4 FIN exome AF: 0.00321

Gnomad4 NFE exome AF: 0.00477

Gnomad4 OTH exome AF: 0.00707

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

Gnomad4 AFR AF: 0.0424

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000349

Gnomad4 EAS AF: 0.00565

Gnomad4 SAS AF: 0.00158

Gnomad4 FIN AF: 0.000121

Gnomad4 NFE AF: 0.000815

Gnomad4 OTH AF: 0.00762

Alfa AF: 0.00527 Hom.: 6

Asia WGS AF: 0.0170 AC: 59 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs79073119; hg19: chr7-107564536;