chr1-209622984-T-A
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMB3 | NM_000228.3 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | Exon 17 of 23 | ENST00000356082.9 | NP_000219.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LAMB3 | ENST00000356082.9 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | Exon 17 of 23 | 1 | NM_000228.3 | ENSP00000348384.3 | ||
LAMB3 | ENST00000367030.7 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | Exon 17 of 23 | 1 | ENSP00000355997.3 | |||
LAMB3 | ENST00000391911.5 | c.2554A>T | p.Met852Leu | missense_variant, splice_region_variant | Exon 16 of 22 | 1 | ENSP00000375778.1 |
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 provided Benign:3
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not specified Benign:2
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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. -
Junctional epidermolysis bullosa, non-Herlitz type Benign:1
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Amelogenesis imperfecta type 1A Benign:1
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Junctional epidermolysis bullosa gravis of Herlitz Benign:1
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Junctional epidermolysis bullosa Benign:1
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