chr8-38172015-A-T

Variant names:

• chr8-38172015-A-T
• rs867224503
• NM_014462.3:c.65T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_014462.3(LSM1):​c.65T>A​(p.Leu22His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L22P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LSM1 NM_014462.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.37
• Publications: 0 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.0017 (below the threshold of 3.09). Trascript score misZ: 0.15829 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LSM1	NM_014462.3	c.65T>A	p.Leu22His	missense_variant	Exon 2 of 4	ENST00000311351.9	NP_055277.1
LSM1	NR_045492.2	n.238T>A		non_coding_transcript_exon_variant	Exon 2 of 3
LSM1	NR_045493.1	n.197T>A		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LSM1	ENST00000311351.9	c.65T>A	p.Leu22His	missense_variant	Exon 2 of 4	1	NM_014462.3	ENSP00000310596.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.7	H;.
PhyloP100		8.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.82		Loss of stability (P = 0.0089);Loss of stability (P = 0.0089);
MVP		0.89
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.94
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs867224503; hg19: chr8-38029533;