18-23890029-C-T

Variant names:

• chr18-23890029-C-T
• rs958631
• NM_198129.4:c.5322C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198129.4(LAMA3):​c.5322C>T​(p.Phe1774Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,613,238 control chromosomes in the GnomAD database, including 3,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1064 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2775 hom.)
• Consequence: LAMA3 NM_198129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.939
• Publications: 14 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 18-23890029-C-T is Benign according to our data. Variant chr18-23890029-C-T is described in ClinVar as Benign. ClinVar VariationId is 255581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.939 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.5322C>T	p.Phe1774Phe	synonymous_variant	Exon 42 of 75	ENST00000313654.14	NP_937762.2
LAMA3	NM_000227.6	c.495C>T	p.Phe165Phe	synonymous_variant	Exon 5 of 38	ENST00000269217.11	NP_000218.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.5322C>T	p.Phe1774Phe	synonymous_variant	Exon 42 of 75	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000269217.11	c.495C>T	p.Phe165Phe	synonymous_variant	Exon 5 of 38	1	NM_000227.6	ENSP00000269217.5

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12430 AN: 152064 Hom.: 1055 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0652

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0705 AC: 17717 AN: 251394 AF XY: 0.0589

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.0607

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0503

GnomAD4 exome AF: 0.0322 AC: 47015 AN: 1461056 Hom.: 2775 Cov.: 31 AF XY: 0.0310 AC XY: 22506 AN XY: 726906

African (AFR) AF: 0.190 AC: 6340 AN: 33418

American (AMR) AF: 0.259 AC: 11561 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 390 AN: 26132

East Asian (EAS) AF: 0.0686 AC: 2722 AN: 39692

South Asian (SAS) AF: 0.0453 AC: 3909 AN: 86224

European-Finnish (FIN) AF: 0.0213 AC: 1138 AN: 53418

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5764

European-Non Finnish (NFE) AF: 0.0167 AC: 18506 AN: 1111322

Other (OTH) AF: 0.0385 AC: 2326 AN: 60364

GnomAD4 genome AF: 0.0820 AC: 12481 AN: 152182 Hom.: 1064 Cov.: 32 AF XY: 0.0838 AC XY: 6232 AN XY: 74392

African (AFR) AF: 0.184 AC: 7641 AN: 41502

American (AMR) AF: 0.178 AC: 2716 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.0652 AC: 337 AN: 5172

South Asian (SAS) AF: 0.0433 AC: 209 AN: 4822

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1129 AN: 68016

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0432 Hom.: 176

Bravo AF: 0.101

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 02, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

May 16, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LAMA3 c.495C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.07 in 251394 control chromosomes, predominantly at a frequency of 0.27 within the Latino subpopulation in the gnomAD database, including 1412 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 597 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA3 causing Junctional Epidermolysis Bullosa phenotype (0.00045), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.495C>T in individuals affected with Junctional Epidermolysis Bullosa and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Mar 04, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laryngo-onycho-cutaneous syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Junctional epidermolysis bullosa gravis of Herlitz Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.6
DANN	Benign	0.84
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs958631; hg19: chr18-21469993; COSMIC: COSV52535427;