rs772038362

Variant names:

• chr18-23939301-C-A
• rs772038362
• NM_198129.4:c.8941C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-23939301-C-A
• chr18-23939301-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198129.4(LAMA3):​c.8941C>A​(p.Gln2981Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056633443).

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.8941C>A	p.Gln2981Lys	missense	Exon 68 of 75	NP_937762.2
	LAMA3	NM_000227.6	MANE Plus Clinical	c.4114C>A	p.Gln1372Lys	missense	Exon 31 of 38	NP_000218.3
	LAMA3	NM_001127717.4		c.8773C>A	p.Gln2925Lys	missense	Exon 67 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.8941C>A	p.Gln2981Lys	missense	Exon 68 of 75	ENSP00000324532.8
	LAMA3	ENST00000269217.11	TSL:1 MANE Plus Clinical	c.4114C>A	p.Gln1372Lys	missense	Exon 31 of 38	ENSP00000269217.5
	LAMA3	ENST00000399516.7	TSL:1	c.8773C>A	p.Gln2925Lys	missense	Exon 67 of 74	ENSP00000382432.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.3
DANN	Benign	0.71
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.13
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.026
Sift	Benign	0.56	T
Sift4G	Benign	0.96	T
Vest4		0.16
MutPred		0.41		Gain of ubiquitination at Q2981 (P = 0.0104)
MVP		0.072
MPC		0.15
ClinPred		0.019	T
GERP RS		3.4
gMVP		0.33
Mutation Taster		=94/6	polymorphism

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: rs772038362; hg19: chr18-21519265;