3-194359450-T-A

Position:

• chr3-194359450-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130830.5(LRRC15):​c.1594A>T​(p.Met532Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRC15 NM_130830.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

Genes affected

LRRC15 (HGNC:20818): (leucine rich repeat containing 15) Enables collagen binding activity; fibronectin binding activity; and laminin binding activity. Involved in negative regulation of protein localization to plasma membrane; positive regulation of cell migration; and receptor-mediated virion attachment to host cell. Located in extracellular exosome. Colocalizes with collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06374067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC15	NM_130830.5	c.1594A>T	p.Met532Leu	missense_variant	2/2	ENST00000347624.4	NP_570843.2
LRRC15	NM_001135057.3	c.1612A>T	p.Met538Leu	missense_variant	3/3		NP_001128529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC15	ENST00000347624.4	c.1594A>T	p.Met532Leu	missense_variant	2/2	1	NM_130830.5	ENSP00000306276.4
LRRC15	ENST00000428839.1	c.1612A>T	p.Met538Leu	missense_variant	3/3	1		ENSP00000413707.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.1612A>T (p.M538L) alteration is located in exon 3 (coding exon 2) of the LRRC15 gene. This alteration results from a A to T substitution at nucleotide position 1612, causing the methionine (M) at amino acid position 538 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.9
DANN	Benign	0.31
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.29	N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.13
MutPred		0.46		Loss of loop (P = 0.0374);.;
MVP		0.28
ClinPred		0.064	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.19

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-194080179;