rs12748250
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000228.3(LAMB3):c.2554A>T(p.Met852Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,612,870 control chromosomes in the GnomAD database, including 17,942 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000228.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMB3 | NM_000228.3 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | 17/23 | ENST00000356082.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMB3 | ENST00000356082.9 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | 17/23 | 1 | NM_000228.3 | P1 | |
LAMB3 | ENST00000367030.7 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | 17/23 | 1 | P1 | ||
LAMB3 | ENST00000391911.5 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | 16/22 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.115 AC: 17436AN: 152072Hom.: 1195 Cov.: 32
GnomAD3 exomes AF: 0.128 AC: 31787AN: 248634Hom.: 2499 AF XY: 0.137 AC XY: 18427AN XY: 134996
GnomAD4 exome AF: 0.146 AC: 213631AN: 1460680Hom.: 16748 Cov.: 34 AF XY: 0.149 AC XY: 107970AN XY: 726668
GnomAD4 genome ? AF: 0.115 AC: 17436AN: 152190Hom.: 1194 Cov.: 32 AF XY: 0.113 AC XY: 8435AN XY: 74412
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 06, 2018 | Variant summary: LAMB3 c.2554A>T (p.Met852Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.13 in 275034 control chromosomes in the gnomAD database, including 2706 homozygotes (gnomAD). The observed variant frequency is approximately 135-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in LAMB3 causing Junctional Epidermolysis Bullosa phenotype (0.00093), strongly suggesting that the variant is benign. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Junctional epidermolysis bullosa, non-Herlitz type Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 08, 2021 | - - |
Amelogenesis imperfecta type 1A Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 08, 2021 | - - |
Junctional epidermolysis bullosa gravis of Herlitz Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 08, 2021 | - - |
Junctional epidermolysis bullosa Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at