3-194642165-G-A

Variant names:

• chr3-194642165-G-A
• rs370741277
• NM_018385.3:c.1880C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018385.3(LSG1):​c.1880C>T​(p.Ala627Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: LSG1 NM_018385.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.862

Genes affected

LSG1 (HGNC:25652): (large 60S subunit nuclear export GTPase 1) This gene encodes a protein related to the yeast large subunit GTPase 1. The encoded protein is necessary for cell viability and may localize in the endoplasmic reticulum, nucleus and cytoplasm.[provided by RefSeq, Feb 2009]

TMEM44-AS2 (HGNC:41082): (TMEM44 antisense RNA 2)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02425623).
• BP6: Variant 3-194642165-G-A is Benign according to our data. Variant chr3-194642165-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2396462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSG1	NM_018385.3	c.1880C>T	p.Ala627Val	missense_variant	Exon 14 of 14	ENST00000265245.10	NP_060855.2
TMEM44-AS2	NR_186047.1	n.241-2510G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSG1	ENST00000265245.10	c.1880C>T	p.Ala627Val	missense_variant	Exon 14 of 14	1	NM_018385.3	ENSP00000265245.5
LSG1	ENST00000475763.5	n.538C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3
TMEM44-AS2	ENST00000447139.2	n.265-2510G>A		intron_variant	Intron 1 of 1	2
LSG1	ENST00000460584.1	n.*8C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151896 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251466 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000759 AC: 111 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000949 AC XY: 69 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151896 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74172

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000947

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.72
DANN	Benign	0.70
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.12	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.014
Sift	Benign	0.40	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.023
MutPred		0.17		Loss of sheet (P = 0.0142);
MVP		0.014
MPC		0.10
ClinPred		0.012	T
GERP RS		-2.8
Varity_R		0.060
gMVP		0.16

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: rs370741277; hg19: chr3-194362894;