chr18-23689909-C-A

Variant names:

• chr18-23689909-C-A
• NM_198129.4:c.226C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198129.4(LAMA3):​c.226C>A​(p.Pro76Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,381,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LAMA3 NM_198129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• junctional epidermolysis bullosa Herlitz type

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12494108).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	NM_198129.4	MANE Select	c.226C>A	p.Pro76Thr	missense	Exon 1 of 75	NP_937762.2	Q16787-2
	LAMA3	NM_001127717.4		c.226C>A	p.Pro76Thr	missense	Exon 1 of 74	NP_001121189.2	A0A0A0MSA0
	LAMA3	NM_001302996.2		c.226C>A	p.Pro76Thr	missense	Exon 1 of 9	NP_001289925.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA3	ENST00000313654.14	TSL:1 MANE Select	c.226C>A	p.Pro76Thr	missense	Exon 1 of 75	ENSP00000324532.8	Q16787-2
	LAMA3	ENST00000399516.7	TSL:1	c.226C>A	p.Pro76Thr	missense	Exon 1 of 74	ENSP00000382432.2	Q16787-3
	LAMA3	ENST00000585600.5	TSL:1	n.226C>A		non_coding_transcript_exon	Exon 1 of 13	ENSP00000468316.1	A0A075B783

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 16 AN: 1381842 Hom.: 0 Cov.: 31 AF XY: 0.0000117 AC XY: 8 AN XY: 681358

African (AFR) AF: 0.00 AC: 0 AN: 29570

American (AMR) AF: 0.00 AC: 0 AN: 34424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24688

East Asian (EAS) AF: 0.00 AC: 0 AN: 33856

South Asian (SAS) AF: 0.00 AC: 0 AN: 77114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.0000149 AC: 16 AN: 1072550

Other (OTH) AF: 0.00 AC: 0 AN: 57384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.68
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.086
Sift	Benign	0.033	D
Vest4		0.28
MutPred		0.41		Gain of phosphorylation at P76 (P = 0.0124)
MVP		0.21
MPC		1.9
ClinPred		0.47	T
GERP RS		2.3
PromoterAI		-0.062	Neutral
gMVP		0.36
Mutation Taster		=80/20	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

hg19: chr18-21269873;