chr4-107895701-C-T

Variant names:

• chr4-107895701-C-T
• rs1560667389
• NM_001375905.1:c.148C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001375905.1(SGMS2):​c.148C>T​(p.Arg50*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGMS2 NM_001375905.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.69
• Publications: 4 publications found

Genes affected

SGMS2 (HGNC:28395): (sphingomyelin synthase 2) Sphingomyelin, a major component of cell and Golgi membranes, is made by the transfer of phosphocholine from phosphatidylcholine onto ceramide, with diacylglycerol as a side product. The protein encoded by this gene is an enzyme that catalyzes this reaction primarily at the cell membrane. The synthesis is reversible, and this enzyme can catalyze the reaction in either direction. The encoded protein is required for cell growth. Three transcript variants encoding the same protein have been found for this gene. There is evidence for more variants, but the full-length nature of their transcripts has not been determined.[provided by RefSeq, Oct 2008]

CYP2U1-AS1 (HGNC:54817): (CYP2U1 and SGMS2 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-107895701-C-T is Pathogenic according to our data. Variant chr4-107895701-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 635285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375905.1. 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
	SGMS2	NM_001375905.1	MANE Select	c.148C>T	p.Arg50*	stop_gained	Exon 3 of 7	NP_001362834.1	Q8NHU3
	SGMS2	NM_001136257.2		c.148C>T	p.Arg50*	stop_gained	Exon 2 of 6	NP_001129729.1	Q8NHU3
	SGMS2	NM_001136258.2		c.148C>T	p.Arg50*	stop_gained	Exon 3 of 7	NP_001129730.1	Q8NHU3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGMS2	ENST00000690982.1	MANE Select	c.148C>T	p.Arg50*	stop_gained	Exon 3 of 7	ENSP00000508566.1	Q8NHU3
	SGMS2	ENST00000359079.8	TSL:1	c.148C>T	p.Arg50*	stop_gained	Exon 2 of 6	ENSP00000351981.4	Q8NHU3
	SGMS2	ENST00000394684.8	TSL:1	c.148C>T	p.Arg50*	stop_gained	Exon 3 of 7	ENSP00000378176.4	Q8NHU3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Calvarial doughnut lesions-bone fragility syndrome (3)
3	-	-	not provided (3)
1	-	-	Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.7
Vest4		0.41
GERP RS		4.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1560667389; hg19: chr4-108816857;