Variant 8-38169798-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000311351.9(LSM1):c.231+4A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000402 in 1,518,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

LSM1
ENST00000311351.9 splice_region, intron

Scores

Splicing: ADA: 0.9974

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.01

Variant links:

Genes affected

LSM1 (HGNC:20472): (LSM1 homolog, mRNA degradation associated) This gene encodes a member of the LSm family of RNA-binding proteins. LSm proteins form stable heteromers that bind specifically to the 3'-terminal oligo(U) tract of U6 snRNA and may play a role in pre-mRNA splicing by mediating U4/U6 snRNP formation. Increased expression of this gene may play a role in cellular transformation and the progression of several malignancies including lung cancer, mesothelioma and breast cancer. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Nov 2011]

LSM1 links:

LSM1 (HGNC:):

LSM1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
LSM1	NM_014462.3 linkuse as main transcript	c.231+4A>C	splice_region_variant, intron_variant	ENST00000311351.9	NP_055277.1	O15116A0A0S2Z590
LSM1	NR_045492.2 linkuse as main transcript	n.288+2167A>C	intron_variant
LSM1	NR_045493.1 linkuse as main transcript	n.363+4A>C	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSM1	ENST00000311351.9 linkuse as main transcript	c.231+4A>C		splice_region_variant, intron_variant		1	NM_014462.3	ENSP00000310596.4		O15116

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000841

AC:

AN:

249688

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134934

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00190

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1365852

Hom.:

Cov.:

AF XY:

0.0000380

AC XY:

AN XY:

684930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000146

Gnomad4 OTH exome

AF:

0.0000525

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000340

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 14, 2020

- -

Constipation;C0010417:Cryptorchidism;C0019294:Inguinal hernia;C0026269:Mitral stenosis;C0038379:Strabismus;C0079924:Oligohydramnios;C0149630:Bicuspid aortic valve;C0232466:Feeding difficulties;C0241397:Triphalangeal thumb;C0265677:Hemivertebrae;C0344925:Perimembranous ventricular septal defect;C0424503:Abnormal facial shape;C0521620:Hydroureter;C1691215:Penile hypospadias;C1858120:Generalized hypotonia;C2317073:Fetal pyelectasis;C3714756:Intellectual disability;C4022738:Neurodevelopmental delay;C4023248:Patent ductus arteriosus after premature birth

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Wendy Chung Laboratory, Columbia University Medical Center

Jan 03, 2019

This variant is classified as VUS since this is the first report associating a human congenital disorder with the gene but the evidence favors pathogenicity and causality. -

Complex neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 28, 2020

The homozygous c.231+4A>C variant in LSM1 was identified by our study in collaboration with the Chung Lab in 2 siblings with multiple congenital anomalies and global developmental delay (PMID: 31010896). This variant has also been reported as a VUS by the Wendy Chung Laboratory in ClinVar (Variation ID: 623485). This variant has been identified in 0.190% (19/10022) of Ashkenazi Jewish chromosomes and 0.002% (2/113204) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775468919). Although this variant has been seen in the general population, its frequency is not high enough to rule out an impact to the protein. In vitro functional studies with patient peripheral blood provide some evidence that the c.231+4A>C variant may slightly impact protein splicing (PMID: 31010896). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools do suggest a weak impact to splicing. However, this information is not predictive enough to determine impact to the protein. The presence of this variant in affected homozygotes increases the likelihood that the c.231+4A>C variant is pathogenic (PMID: 31010896). Furthermore, although this gene has been reported in association with multiple congenital anomalies and global developmental delay, it currently has limited evidence for these associations. In summary, the clinical significance of the c.231+4A>C variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over