Genetic Variant LSM7:p.Asp41Tyr (chr19-2324173-C-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_Strong

The NM_016199.3(LSM7):c.121G>T(p.Asp41Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000028 in 1,430,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D41N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

LSM7
NM_016199.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.61

Publications

0 publications found

Variant links:

Genes affected

LSM7 (HGNC:20470): (LSM7 homolog, U6 small nuclear RNA and mRNA degradation associated) Sm-like proteins were identified in a variety of organisms based on sequence homology with the Sm protein family (see SNRPD2; MIM 601061). Sm-like proteins contain the Sm sequence motif, which consists of 2 regions separated by a linker of variable length that folds as a loop. The Sm-like proteins are thought to form a stable heteromer present in tri-snRNP particles, which are important for pre-mRNA splicing.[supplied by OMIM, Apr 2004]

LSM7 links:

ENSG00000273734 (HGNC:):

ENSG00000273734 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-2324173-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 996070.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.4328 (below the threshold of 3.09). Trascript score misZ: -0.025562 (below the threshold of 3.09).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016199.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSM7	NM_016199.3	MANE Select	c.121G>T	p.Asp41Tyr	missense	Exon 3 of 4	NP_057283.1	Q9UK45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LSM7	ENST00000252622.15	TSL:1 MANE Select	c.121G>T	p.Asp41Tyr	missense	Exon 3 of 4	ENSP00000252622.8	Q9UK45
LSM7	ENST00000587502.2	TSL:1	c.-42G>T		5_prime_UTR	Exon 2 of 3	ENSP00000485007.1	A0A087X2I5
ENSG00000273734	ENST00000621615.1	TSL:2	n.147-10429C>A		intron	N/A	ENSP00000481965.1	A0A087WYN8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1430040

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

708366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32684

American (AMR)

AF:

0.00

AC:

AN:

40058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25622

East Asian (EAS)

AF:

0.00

AC:

AN:

37990

South Asian (SAS)

AF:

0.00

AC:

AN:

81386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1096376

Other (OTH)

AF:

0.00

AC:

AN:

59230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

5.2

PhyloP100

6.6

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.3

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.94

Loss of ubiquitination at K38 (P = 0.1264)

MVP

0.96

MPC

2.2

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.96

Mutation Taster

=12/88

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over