18-23816593-C-T

Variant names:

• chr18-23816593-C-T
• rs12608087
• NM_198129.4:c.2147+106C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198129.4(LAMA3):​c.2147+106C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 921,264 control chromosomes in the GnomAD database, including 12,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1927 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10112 hom.)
• Consequence: LAMA3 NM_198129.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0380
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-23816593-C-T is Benign according to our data. Variant chr18-23816593-C-T is described in ClinVar as [Benign]. Clinvar id is 1274779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMA3	NM_198129.4	c.2147+106C>T		intron_variant	Intron 18 of 74	ENST00000313654.14	NP_937762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMA3	ENST00000313654.14	c.2147+106C>T		intron_variant	Intron 18 of 74	1	NM_198129.4	ENSP00000324532.8
LAMA3	ENST00000399516.7	c.2147+106C>T		intron_variant	Intron 18 of 73	1		ENSP00000382432.2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19715 AN: 152002 Hom.: 1929 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.0832

Gnomad OTH AF: 0.154

GnomAD4 exome AF: 0.122 AC: 93639 AN: 769144 Hom.: 10112 AF XY: 0.125 AC XY: 50211 AN XY: 403282

African (AFR) AF: 0.153 AC: 3030 AN: 19852

American (AMR) AF: 0.150 AC: 5343 AN: 35534

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2456 AN: 21268

East Asian (EAS) AF: 0.568 AC: 18890 AN: 33258

South Asian (SAS) AF: 0.192 AC: 12943 AN: 67246

European-Finnish (FIN) AF: 0.0898 AC: 3458 AN: 38514

Middle Eastern (MID) AF: 0.201 AC: 900 AN: 4488

European-Non Finnish (NFE) AF: 0.0812 AC: 41488 AN: 511250

Other (OTH) AF: 0.136 AC: 5131 AN: 37734

GnomAD4 genome AF: 0.130 AC: 19720 AN: 152120 Hom.: 1927 Cov.: 32 AF XY: 0.135 AC XY: 10074 AN XY: 74368

African (AFR) AF: 0.151 AC: 6245 AN: 41488

American (AMR) AF: 0.136 AC: 2073 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3470

East Asian (EAS) AF: 0.567 AC: 2924 AN: 5156

South Asian (SAS) AF: 0.202 AC: 972 AN: 4822

European-Finnish (FIN) AF: 0.0929 AC: 984 AN: 10588

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.0832 AC: 5660 AN: 68008

Other (OTH) AF: 0.154 AC: 323 AN: 2104

Alfa AF: 0.0952 Hom.: 1407

Bravo AF: 0.137

Asia WGS AF: 0.353 AC: 1225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.27
PhyloP100		-0.038
Mutation Taster		=100/0	polymorphism (auto)

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: rs12608087; hg19: chr18-21396557; COSMIC: COSV107376958;