chr8-38169798-T-G

Variant names:

• chr8-38169798-T-G
• rs775468919
• NM_014462.3:c.231+4A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_014462.3(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 NM_014462.3 splice_region, intron
• Scores: Splicing: ADA: 0.9974
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 5.01
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSM1	NM_014462.3	c.231+4A>C		splice_region_variant, intron_variant	Intron 3 of 3	ENST00000311351.9	NP_055277.1
LSM1	NR_045492.2	n.288+2167A>C		intron_variant	Intron 2 of 2
LSM1	NR_045493.1	n.363+4A>C		splice_region_variant, intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSM1	ENST00000311351.9	c.231+4A>C		splice_region_variant, intron_variant	Intron 3 of 3	1	NM_014462.3	ENSP00000310596.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000841 AC: 21 AN: 249688 AF XY: 0.0000741

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 57 AN: 1365852 Hom.: 0 Cov.: 22 AF XY: 0.0000380 AC XY: 26 AN XY: 684930

African (AFR) AF: 0.00 AC: 0 AN: 31540

American (AMR) AF: 0.0000226 AC: 1 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 38 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 83966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.0000146 AC: 15 AN: 1025254

Other (OTH) AF: 0.0000525 AC: 3 AN: 57184

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 07, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jan 03, 2019

Wendy Chung Laboratory, Boston Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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

May 28, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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	24
DANN	Uncertain	0.98
PhyloP100		5.0
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs775468919; hg19: chr8-38027316;