6-63280226-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016571.3(LGSN):c.1325A>G(p.Asp442Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,204 control chromosomes in the GnomAD database, including 81 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (34 hom.)
• Consequence: LGSN NM_016571.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.822

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00319916).
• BP6: Variant 6-63280226-T-C is Benign according to our data. Variant chr6-63280226-T-C is described in ClinVar as [Benign]. Clinvar id is 783466.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2061/152314) while in subpopulation AFR AF= 0.0466 (1935/41562). AF 95% confidence interval is 0.0448. There are 47 homozygotes in gnomad4. There are 981 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGSN	NM_016571.3	c.1325A>G	p.Asp442Gly	missense_variant	4/4	ENST00000370657.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGSN	ENST00000370657.9	c.1325A>G	p.Asp442Gly	missense_variant	4/4	1	NM_016571.3	P1
LGSN	ENST00000370658.9	c.*277A>G		3_prime_UTR_variant	5/5	1
LGSN	ENST00000622415.1	c.*1050A>G		3_prime_UTR_variant	5/5	2
LGSN	ENST00000485906.6	c.529+796A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2055 AN: 152196 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00346 AC: 870 AN: 251422 Hom.: 13 AF XY: 0.00254 AC XY: 345 AN XY: 135878

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00129 AC: 1888 AN: 1461890 Hom.: 34 Cov.: 33 AF XY: 0.00107 AC XY: 778 AN XY: 727244

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.0135 AC: 2061 AN: 152314 Hom.: 47 Cov.: 32 AF XY: 0.0132 AC XY: 981 AN XY: 74484

Gnomad4 AFR AF: 0.0466

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00606 Hom.: 6

Bravo AF: 0.0155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00404 AC: 490

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	2.0
Dann	Benign	0.61
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.51
MPC		0.013
ClinPred		0.0015	T
GERP RS		2.2
Varity_R		0.068
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs35039535; hg19: chr6-63990131;