1-209634515-G-C

Position:

• chr1-209634515-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The ENST00000356082.9(LAMB3):​c.496C>G​(p.Gln166Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q166?) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LAMB3 ENST00000356082.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77

Genes affected

LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-209634513-CT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1724715.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13747472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.496C>G	p.Gln166Glu	missense_variant	6/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.496C>G	p.Gln166Glu	missense_variant	6/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7	c.496C>G	p.Gln166Glu	missense_variant	6/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5	c.496C>G	p.Gln166Glu	missense_variant	5/22	1		ENSP00000375778	P1
LAMB3	ENST00000415782.1	c.496C>G	p.Gln166Glu	missense_variant	6/6	2		ENSP00000388960

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	.;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.028	B;B;B;.
Vest4		0.079
MutPred		0.48		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.79
MPC		0.13
ClinPred		0.12	T
GERP RS		2.6
Varity_R		0.12
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121912483; hg19: chr1-209807860;