chr6-112214000-C-T

Variant names:

• chr6-112214000-C-T
• rs75992359
• ENST00000431543.6:c.368G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000431543.6(LAMA4):​c.368G>A​(p.Arg123Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 758,944 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (89 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (42 hom.)
• Consequence: LAMA4 ENST00000431543.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.722
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020734668).
• BP6: Variant 6-112214000-C-T is Benign according to our data. Variant chr6-112214000-C-T is described in ClinVar as Benign. ClinVar VariationId is 192187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000431543.6. 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.297+2368G>A		intron	N/A	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.297+2368G>A		intron	N/A	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.297+2368G>A		intron	N/A	NP_002281.3	Q16363-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMA4	ENST00000431543.6	TSL:1	c.368G>A	p.Arg123Lys	missense	Exon 4 of 4	ENSP00000412136.2	Q6LET9
	LAMA4	ENST00000230538.12	TSL:1 MANE Select	c.297+2368G>A		intron	N/A	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.297+2368G>A		intron	N/A	ENSP00000374114.4	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2948 AN: 152138 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00553 AC: 1279 AN: 231458 AF XY: 0.00460

Gnomad AFR exome AF: 0.0618

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000736

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00361 AC: 2192 AN: 606688 Hom.: 42 Cov.: 0 AF XY: 0.00299 AC XY: 991 AN XY: 331970

African (AFR) AF: 0.0583 AC: 983 AN: 16874

American (AMR) AF: 0.00426 AC: 173 AN: 40610

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 528 AN: 20442

East Asian (EAS) AF: 0.00 AC: 0 AN: 34856

South Asian (SAS) AF: 0.000210 AC: 14 AN: 66760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51398

Middle Eastern (MID) AF: 0.00417 AC: 17 AN: 4074

European-Non Finnish (NFE) AF: 0.000635 AC: 216 AN: 339894

Other (OTH) AF: 0.00821 AC: 261 AN: 31780

GnomAD4 genome AF: 0.0194 AC: 2960 AN: 152256 Hom.: 89 Cov.: 32 AF XY: 0.0186 AC XY: 1382 AN XY: 74460

African (AFR) AF: 0.0634 AC: 2632 AN: 41524

American (AMR) AF: 0.00954 AC: 146 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68020

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0481 Hom.: 2406

Bravo AF: 0.0219

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0576 AC: 101

ESP6500EA AF: 0.00151 AC: 6

ExAC AF: 0.00575 AC: 667

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.7
DANN	Benign	0.87
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.72
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.025
Sift	Pathogenic	0.0	D
Polyphen		0.021	B
Vest4		0.068
MVP		0.34
ClinPred		0.022	T
GERP RS		-0.86
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: rs75992359; hg19: chr6-112535201;