6-112185279-C-T

Variant names:

• chr6-112185279-C-T
• rs147069572
• NM_001105206.3:c.1035G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001105206.3(LAMA4):​c.1035G>A​(p.Thr345Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 1,613,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T345T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: LAMA4 NM_001105206.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.285
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.109).
• BP6: Variant 6-112185279-C-T is Benign according to our data. Variant chr6-112185279-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.285 with no splicing effect.
• BS2: High AC in GnomAd4 at 92 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.1035G>A	p.Thr345Thr	synonymous	Exon 9 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.1014G>A	p.Thr338Thr	synonymous	Exon 9 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.1014G>A	p.Thr338Thr	synonymous	Exon 9 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.1035G>A	p.Thr345Thr	synonymous	Exon 9 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.1014G>A	p.Thr338Thr	synonymous	Exon 9 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.1014G>A	p.Thr338Thr	synonymous	Exon 9 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000716 AC: 180 AN: 251360 AF XY: 0.000729

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00522

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000660 AC: 965 AN: 1461158 Hom.: 0 Cov.: 31 AF XY: 0.000638 AC XY: 464 AN XY: 726946

African (AFR) AF: 0.000179 AC: 6 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86240

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000732 AC: 814 AN: 1111366

Other (OTH) AF: 0.000514 AC: 31 AN: 60362

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74490

African (AFR) AF: 0.000577 AC: 24 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00424 AC: 22 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000589 Hom.: 0

Bravo AF: 0.000604

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Dilated cardiomyopathy 1JJ (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.1
DANN	Benign	0.74
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs147069572; hg19: chr6-112506481; COSMIC: COSV57892744; COSMIC: COSV57892744;