1-209637948-T-C

Position:

• chr1-209637948-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000228.3(LAMB3):​c.332A>G​(p.Asp111Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000387 in 1,613,360 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: LAMB3 NM_000228.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.82

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007794291).
• BP6: Variant 1-209637948-T-C is Benign according to our data. Variant chr1-209637948-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255594.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00217 (330/152214) while in subpopulation AFR AF= 0.00754 (313/41518). AF 95% confidence interval is 0.00685. There are 3 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMB3	NM_000228.3	c.332A>G	p.Asp111Gly	missense_variant	5/23	ENST00000356082.9	NP_000219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMB3	ENST00000356082.9	c.332A>G	p.Asp111Gly	missense_variant	5/23	1	NM_000228.3	ENSP00000348384	P1
LAMB3	ENST00000367030.7	c.332A>G	p.Asp111Gly	missense_variant	5/23	1		ENSP00000355997	P1
LAMB3	ENST00000391911.5	c.332A>G	p.Asp111Gly	missense_variant	4/22	1		ENSP00000375778	P1
LAMB3	ENST00000415782.1	c.332A>G	p.Asp111Gly	missense_variant	5/6	2		ENSP00000388960

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152096 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000504 AC: 126 AN: 249806 Hom.: 0 AF XY: 0.000385 AC XY: 52 AN XY: 135036

Gnomad AFR exome AF: 0.00753

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461146 Hom.: 2 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 726828

Gnomad4 AFR exome AF: 0.00771

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152214 Hom.: 3 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74424

Gnomad4 AFR AF: 0.00754

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.00261

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000741 AC: 90

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The LAMB3 p.Asp111Gly variant was not identified in the literature but was identified in dbSNP (ID: rs55824996), ClinVar (classified as likely benign by Prevention Genetics and benign by Invitae), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 188 of 281174 chromosomes (2 homozygous) at a frequency of 0.0006686 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 181 of 24632 chromosomes (freq: 0.007348), Latino in 6 of 35264 chromosomes (freq: 0.00017) and European (non-Finnish) in 1 of 128524 chromosomes (freq: 0.000008), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Asp111 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2022	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	.;T;.;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.2	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;T
Polyphen		0.99	D;D;D;.
Vest4		0.41
MVP		0.88
MPC		0.20
ClinPred		0.063	T
GERP RS		4.1
Varity_R		0.40
gMVP		0.53

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: rs55824996; hg19: chr1-209811293;