6-112109459-A-G

Variant names:

• chr6-112109459-A-G
• rs144482486
• NM_001105206.3:c.5450T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001105206.3(LAMA4):​c.5450T>C​(p.Ile1817Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 8.18
• Publications: 2 publications found

Genes affected

LAMA4 (HGNC:6484): (laminin subunit alpha 4) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the alpha chain isoform laminin, alpha 4. The domain structure of alpha 4 is similar to that of alpha 3, both of which resemble truncated versions of alpha 1 and alpha 2, in that approximately 1,200 residues at the N-terminus (domains IV, V and VI) have been lost. Laminin, alpha 4 contains the C-terminal G domain which distinguishes all alpha chains from the beta and gamma chains. The RNA analysis from adult and fetal tissues revealed developmental regulation of expression, however, the exact function of laminin, alpha 4 is not known. Tissue-specific utilization of alternative polyA-signal has been described in literature. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

LAMA4 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1JJ

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007759601).
• BP6: Variant 6-112109459-A-G is Benign according to our data. Variant chr6-112109459-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 313 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105206.3. 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
	LAMA4	NM_001105206.3	MANE Select	c.5450T>C	p.Ile1817Thr	missense	Exon 39 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.5429T>C	p.Ile1810Thr	missense	Exon 39 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.5429T>C	p.Ile1810Thr	missense	Exon 39 of 39	NP_002281.3	Q16363-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.5450T>C	p.Ile1817Thr	missense	Exon 39 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.5429T>C	p.Ile1810Thr	missense	Exon 39 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.5429T>C	p.Ile1810Thr	missense	Exon 39 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152150 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00741

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000566 AC: 142 AN: 251096 AF XY: 0.000435

Gnomad AFR exome AF: 0.00787

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000194 AC: 283 AN: 1461706 Hom.: 1 Cov.: 31 AF XY: 0.000162 AC XY: 118 AN XY: 727152

African (AFR) AF: 0.00708 AC: 237 AN: 33470

American (AMR) AF: 0.000425 AC: 19 AN: 44700

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5718

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111956

Other (OTH) AF: 0.000265 AC: 16 AN: 60378

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152268 Hom.: 3 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74456

African (AFR) AF: 0.00734 AC: 305 AN: 41554

American (AMR) AF: 0.000393 AC: 6 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000908 Hom.: 2

Bravo AF: 0.00251

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Dilated cardiomyopathy 1JJ (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LAMA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.67	T
PhyloP100		8.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.49
Sift	Benign	0.038	D
Sift4G	Uncertain	0.0040	D
Vest4		0.46
MVP		0.84
MPC		0.41
ClinPred		0.023	T
GERP RS		6.2
gMVP		0.60
Mutation Taster		=98/2	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: rs144482486; hg19: chr6-112430662;