6-112158839-A-G

Variant names:

• chr6-112158839-A-G
• rs3752577
• NM_001105206.3:c.1710T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001105206.3(LAMA4):​c.1710T>C​(p.Ser570Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,611,908 control chromosomes in the GnomAD database, including 8,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (782 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7471 hom.)
• Consequence: LAMA4 NM_001105206.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.376
• Publications: 21 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

ENSG00000237234 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 6-112158839-A-G is Benign according to our data. Variant chr6-112158839-A-G is described in ClinVar as Benign. ClinVar VariationId is 44351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.376 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

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.1710T>C	p.Ser570Ser	synonymous	Exon 14 of 39	NP_001098676.2	Q16363-1
	LAMA4	NM_001105207.3		c.1689T>C	p.Ser563Ser	synonymous	Exon 14 of 39	NP_001098677.2	A0A0A0MTC7
	LAMA4	NM_002290.5		c.1689T>C	p.Ser563Ser	synonymous	Exon 14 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.1710T>C	p.Ser570Ser	synonymous	Exon 14 of 39	ENSP00000230538.7	Q16363-1
	LAMA4	ENST00000389463.9	TSL:1	c.1689T>C	p.Ser563Ser	synonymous	Exon 14 of 39	ENSP00000374114.4	A0A0A0MTC7
	LAMA4	ENST00000522006.5	TSL:1	c.1689T>C	p.Ser563Ser	synonymous	Exon 14 of 39	ENSP00000429488.1	A0A0A0MTC7

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13389 AN: 152094 Hom.: 784 Cov.: 32

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0986

Gnomad OTH AF: 0.0707

GnomAD2 exomes AF: 0.107 AC: 26756 AN: 251066 AF XY: 0.106

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0732

Gnomad EAS exome AF: 0.0975

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.0970

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0951 AC: 138880 AN: 1459696 Hom.: 7471 Cov.: 30 AF XY: 0.0964 AC XY: 70039 AN XY: 726272

African (AFR) AF: 0.0395 AC: 1321 AN: 33450

American (AMR) AF: 0.130 AC: 5801 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 1826 AN: 26114

East Asian (EAS) AF: 0.158 AC: 6251 AN: 39660

South Asian (SAS) AF: 0.110 AC: 9445 AN: 86214

European-Finnish (FIN) AF: 0.181 AC: 9668 AN: 53360

Middle Eastern (MID) AF: 0.0692 AC: 399 AN: 5762

European-Non Finnish (NFE) AF: 0.0891 AC: 98934 AN: 1110092

Other (OTH) AF: 0.0868 AC: 5235 AN: 60330

GnomAD4 genome AF: 0.0880 AC: 13395 AN: 152212 Hom.: 782 Cov.: 32 AF XY: 0.0930 AC XY: 6920 AN XY: 74410

African (AFR) AF: 0.0414 AC: 1719 AN: 41540

American (AMR) AF: 0.0905 AC: 1383 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3468

East Asian (EAS) AF: 0.122 AC: 633 AN: 5190

South Asian (SAS) AF: 0.108 AC: 519 AN: 4820

European-Finnish (FIN) AF: 0.185 AC: 1956 AN: 10590

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0986 AC: 6708 AN: 68004

Other (OTH) AF: 0.0724 AC: 153 AN: 2114

Alfa AF: 0.0876 Hom.: 1354

Bravo AF: 0.0767

Asia WGS AF: 0.123 AC: 427 AN: 3478

EpiCase AF: 0.0847

EpiControl AF: 0.0851

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.1
DANN	Benign	0.82
PhyloP100		0.38
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: rs3752577; hg19: chr6-112480041; COSMIC: COSV57893922; COSMIC: COSV57893922;