19-2321786-C-G

Variant names:

• chr19-2321786-C-G
• rs753556902
• NM_016199.3:c.206G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_016199.3(LSM7):​c.206G>C​(p.Arg69Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSM7 NM_016199.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.51
• Publications: 1 publications found

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]

ENSG00000273734 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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 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, 0.941
• PP5: Variant 19-2321786-C-G is Pathogenic according to our data. Variant chr19-2321786-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 996338.Status of the report is criteria_provided_single_submitter, 1 stars.

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.206G>C	p.Arg69Pro	missense	Exon 4 of 4	NP_057283.1	Q9UK45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LSM7	ENST00000252622.15	TSL:1 MANE Select	c.206G>C	p.Arg69Pro	missense	Exon 4 of 4	ENSP00000252622.8	Q9UK45
	LSM7	ENST00000587502.2	TSL:1	c.44G>C	p.Arg15Pro	missense	Exon 3 of 3	ENSP00000485007.1	A0A087X2I5
	ENSG00000273734	ENST00000621615.1	TSL:2	n.147-12816C>G		intron	N/A	ENSP00000481965.1	A0A087WYN8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	In utero death (1)
1	-	-	Joubert syndrome 36 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		5.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.78		Loss of stability (P = 0.1016)
MVP		0.84
MPC		2.4
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.95
Mutation Taster		=29/71	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: rs753556902; hg19: chr19-2321785;