rs61752346

Variant names:

• chr18-23933924-C-T
• rs61752346
• NM_198129.4:c.8851C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198129.4(LAMA3):​c.8851C>T​(p.Arg2951Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,022 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2951H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.284
• Publications: 7 publications found

Genes affected

LAMA3 (HGNC:6483): (laminin subunit alpha 3) The protein encoded by this gene belongs to the laminin family of secreted molecules. Laminins are heterotrimeric molecules that consist of alpha, beta, and gamma subunits that assemble through a coiled-coil domain. Laminins are essential for formation and function of the basement membrane and have additional functions in regulating cell migration and mechanical signal transduction. This gene encodes an alpha subunit and is responsive to several epithelial-mesenchymal regulators including keratinocyte growth factor, epidermal growth factor and insulin-like growth factor. Mutations in this gene have been identified as the cause of Herlitz type junctional epidermolysis bullosa and laryngoonychocutaneous syndrome. Alternative splicing and alternative promoter usage result in multiple transcript variants. [provided by RefSeq, Dec 2014]

LAMA3 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• laryngo-onycho-cutaneous syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• junctional epidermolysis bullosa Herlitz type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075652897).
• BP6: Variant 18-23933924-C-T is Benign according to our data. Variant chr18-23933924-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 555996.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00258 (3766/1461742) while in subpopulation NFE AF = 0.00326 (3623/1111926). AF 95% confidence interval is 0.00317. There are 10 homozygotes in GnomAdExome4. There are 1761 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.8851C>T	p.Arg2951Cys	missense	Exon 67 of 75	NP_937762.2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.4024C>T	p.Arg1342Cys	missense	Exon 30 of 38	NP_000218.3
	LAMA3	NM_001127717.4		c.8683C>T	p.Arg2895Cys	missense	Exon 66 of 74	NP_001121189.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.8851C>T	p.Arg2951Cys	missense	Exon 67 of 75	ENSP00000324532.8
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.4024C>T	p.Arg1342Cys	missense	Exon 30 of 38	ENSP00000269217.5
	LAMA3	ENST00000399516.7	TSL:1	c.8683C>T	p.Arg2895Cys	missense	Exon 66 of 74	ENSP00000382432.2

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00104 AC: 261 AN: 251434 AF XY: 0.00107

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00258 AC: 3766 AN: 1461742 Hom.: 10 Cov.: 32 AF XY: 0.00242 AC XY: 1761 AN XY: 727178

African (AFR) AF: 0.000388 AC: 13 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53412

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.00326 AC: 3623 AN: 1111926

Other (OTH) AF: 0.00141 AC: 85 AN: 60392

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74474

African (AFR) AF: 0.000650 AC: 27 AN: 41554

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00153

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00124

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Junctional epidermolysis bullosa gravis of Herlitz (2)
-	1	-	Laryngo-onycho-cutaneous syndrome (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	3.8
DANN	Benign	0.90
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.061	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.28
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.24
Sift	Benign	0.037	D
Sift4G	Benign	0.15	T
Vest4		0.17
MVP		0.15
MPC		0.27
ClinPred		0.015	T
GERP RS		1.0
gMVP		0.42
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs61752346; hg19: chr18-21513888; COSMIC: COSV52533639; COSMIC: COSV52533639;