rs796051883

Positions:

• chr1-209650014-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000356082.9(LAMB3):​c.133T>G​(p.Ser45Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. S45S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAMB3 ENST00000356082.9 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.01

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.133T>G	p.Ser45Ala	missense_variant	3/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.133T>G	p.Ser45Ala	missense_variant	3/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7	c.133T>G	p.Ser45Ala	missense_variant	3/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5	c.133T>G	p.Ser45Ala	missense_variant	2/22	1		ENSP00000375778	P1
LAMB3	ENST00000415782.1	c.133T>G	p.Ser45Ala	missense_variant	3/6	2		ENSP00000388960

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lyon Laboratory, Cold Spring Harbor Laboratory

Jul 05, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	.;T;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Pathogenic	3.5	H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.54
MutPred		0.75		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.91
MPC		0.49
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.56
gMVP		0.63

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: rs796051883; hg19: chr1-209823359;