12-54631775-C-A

Position:

• chr12-54631775-C-A

Variant summary

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

The ENST00000257867.5(LACRT):​c.318G>T​(p.Met106Ile) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M106R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LACRT ENST00000257867.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.355

Genes affected

LACRT (HGNC:16430): (lacritin) The protein encoded by this gene is highly expressed in the lacrimal glands and localized primarily to secretory granules and secretory fluid. It augments lacrimal acinar cell secretion, promotes ductal cell proliferation, and stimulates signaling through tyrosine phosphorylation and release of calcium. [provided by RefSeq, Jul 2008]

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=0.06231129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LACRT	NM_033277.2	c.318G>T	p.Met106Ile	missense_variant	4/5	ENST00000257867.5	NP_150593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LACRT	ENST00000257867.5	c.318G>T	p.Met106Ile	missense_variant	4/5	1	NM_033277.2	ENSP00000257867	P2
LACRT	ENST00000547511.5	c.285G>T	p.Met95Ile	missense_variant	4/5	3		ENSP00000447536	A2
LACRT	ENST00000546721.5	c.195G>T	p.Met65Ile	missense_variant	3/4	5		ENSP00000448193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 18, 2022

The c.318G>T (p.M106I) alteration is located in exon 4 (coding exon 4) of the LACRT gene. This alteration results from a G to T substitution at nucleotide position 318, causing the methionine (M) at amino acid position 106 to be replaced by an isoleucine (I). 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	0.22
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.17
DANN	Benign	0.45
DEOGEN2	Benign	0.011	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.062	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.23	T;.;.
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.10, 0.10
MutPred		0.29		.;.;Gain of catalytic residue at G109 (P = 0.0018);
MVP		0.085
MPC		0.010
ClinPred		0.027	T
GERP RS		-0.54
Varity_R		0.15
gMVP		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-55025559; COSMIC: COSV99143786; COSMIC: COSV99143786;