6-63280875-A-T

Position:

• chr6-63280875-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016571.3(LGSN):​c.676T>A​(p.Phe226Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGSN NM_016571.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

Genes affected

LGSN (HGNC:21016): (lengsin, lens protein with glutamine synthetase domain) This gene encodes a protein with similarity to the GS I members of the glutamine synthetase superfamily. The encoded protein is referred to as a pseudo-glutamine synthetase because it has no glutamine synthesis activity and may function as a chaperone protein. This protein is localized to the lens and may be associated with cataract disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGSN	NM_016571.3	c.676T>A	p.Phe226Ile	missense_variant	4/4	ENST00000370657.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGSN	ENST00000370657.9	c.676T>A	p.Phe226Ile	missense_variant	4/4	1	NM_016571.3	P1
LGSN	ENST00000370658.9	c.529+147T>A		intron_variant		1
LGSN	ENST00000622415.1	c.*401T>A		3_prime_UTR_variant	5/5	2
LGSN	ENST00000485906.6	c.529+147T>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Feb 06, 2024

The c.676T>A (p.F226I) alteration is located in exon 4 (coding exon 4) of the LGSN gene. This alteration results from a T to A substitution at nucleotide position 676, causing the phenylalanine (F) at amino acid position 226 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	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.52
Sift	Benign	0.14	T
Sift4G	Benign	0.081	T
Polyphen		0.73	P
Vest4		0.66
MutPred		0.65		Loss of loop (P = 0.1242);
MVP		0.82
MPC		0.027
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.55
gMVP		0.78

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: chr6-63990780;