chr4-107895701-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. 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

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• 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 [Likely_pathogenic]. Clinvar id is 635285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-107895701-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGMS2	NM_001375905.1	c.148C>T	p.Arg50*	stop_gained	Exon 3 of 7	ENST00000690982.1	NP_001362834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGMS2	ENST00000690982.1	c.148C>T	p.Arg50*	stop_gained	Exon 3 of 7		NM_001375905.1	ENSP00000508566.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: impaired localization to the plasma membrane and abolished enzyme activity (Pekkinen et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19839042, 31064048, 31004177, 30779713, 32028018, 34504906, 34761145) -

Dec 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg50*) in the SGMS2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SGMS2 cause disease. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with doughnut lesion of calvaria and bone fragility syndrome (PMID: 30779713, 32028018). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 635285). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SGMS2 function (PMID: 30779713). For these reasons, this variant has been classified as Pathogenic. -

Calvarial doughnut lesions-bone fragility syndrome Pathogenic:3

Aug 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia Pathogenic:1

Dec 10, 2021

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 27, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.41
GERP RS		4.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs1560667389; hg19: chr4-108816857;