8-38169915-T-A

Position:

• chr8-38169915-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_014462.3(LSM1):​c.118A>T​(p.Asn40Tyr) variant causes a missense, splice region 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. 12/21 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LSM1 NM_014462.3 missense, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.84

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 8-38169915-T-A is Pathogenic according to our data. Variant chr8-38169915-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1691228.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSM1	NM_014462.3	c.118A>T	p.Asn40Tyr	missense_variant, splice_region_variant	3/4	ENST00000311351.9	NP_055277.1
LSM1	NR_045493.1	n.250A>T		splice_region_variant, non_coding_transcript_exon_variant	3/4
LSM1	NR_045492.2	n.288+2050A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSM1	ENST00000311351.9	c.118A>T	p.Asn40Tyr	missense_variant, splice_region_variant	3/4	1	NM_014462.3	ENSP00000310596.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Global developmental delay Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Department Of Medical Genetics, Faculty Of Medicine, Ege University

-

The c.118A>T substitution causes a missense replacement of the 40th amino acid of LSM1 mRNA (asparagine to tyrosine) in exon 3 of the gene. In-silico predictions were aggregated deleterious for the replacement. The variant had not previously been reported in the public databases. Regarding these findings, the c.118A>T (p.Asn40Tyr variant) in LSM1 was classified as a variant of unknown significance (VUS) according to the recommendations of the American College of Medical Genetics (ACMG) Standards and Guidelines. The parents were found to be heterozygous for the same variant via segregation analysis. After the segregation of the family, variant was interpreted as likely pathogenic according to the ACMG classification. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.9	H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Gain of sheet (P = 0.1208);
MVP		0.89
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38027433;