rs397516720

chr6-112154908-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001105206.3(LAMA4):c.1999G>T(p.Asp667Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,613,518 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: LAMA4 NM_001105206.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 3.22

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008079559).
• BP6: Variant 6-112154908-C-A is Benign according to our data. Variant chr6-112154908-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 44357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-112154908-C-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMA4	NM_001105206.3	c.1999G>T	p.Asp667Tyr	missense_variant	16/39	ENST00000230538.12
LOC107986633	XR_001744299.2	n.440-412C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMA4	ENST00000230538.12	c.1999G>T	p.Asp667Tyr	missense_variant	16/39	1	NM_001105206.3	A1
	ENST00000585373.5	n.144C>A		non_coding_transcript_exon_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000947 AC: 238 AN: 251238 Hom.: 2 AF XY: 0.00130 AC XY: 177 AN XY: 135782

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00706

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000512 AC: 748 AN: 1461252 Hom.: 7 Cov.: 29 AF XY: 0.000735 AC XY: 534 AN XY: 726984

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00735

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74462

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00114 AC: 139

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2021	The p.Asp660Tyr variant in LAMA4 is classified as benign because it has been identified in 0.7% (216/30610) of South Asian chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 29, 2014

- -

Dilated cardiomyopathy 1JJ Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.051	T;T;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;.;.;D
MetaRNN	Benign	0.0081	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.87	N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Benign	0.078	T;T;T;T
Vest4		0.57
MutPred		0.32		Loss of disorder (P = 0.0549);.;.;.;
MVP		0.42
MPC		0.57
ClinPred		0.088	T
GERP RS		5.2
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516720; hg19: chr6-112476110; COSMIC: COSV57905000; COSMIC: COSV57905000;