6-109443363-A-G

Variant names:

• chr6-109443363-A-G
• NM_003080.3:c.826A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003080.3(SMPD2):​c.826A>G​(p.Met276Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMPD2 NM_003080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38

Genes affected

SMPD2 (HGNC:11121): (sphingomyelin phosphodiesterase 2) This gene encodes a protein which was initially identified as a sphingomyelinase based on sequence similarity between bacterial sphingomyelinases and a yeast protein. Subsequent studies showed that its biological function is less likely to be as a sphingomyelinase and instead as a lysophospholipase. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD2	NM_003080.3	c.826A>G	p.Met276Val	missense_variant	Exon 9 of 10	ENST00000258052.8	NP_003071.2
SMPD2	XM_011536079.2	c.511A>G	p.Met171Val	missense_variant	Exon 7 of 8		XP_011534381.1
SMPD2	XR_942566.3	n.1159A>G		non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD2	ENST00000258052.8	c.826A>G	p.Met276Val	missense_variant	Exon 9 of 10	1	NM_003080.3	ENSP00000258052.3
SMPD2	ENST00000458487.1	c.514A>G	p.Met172Val	missense_variant	Exon 3 of 4	2		ENSP00000399731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826A>G (p.M276V) alteration is located in exon 9 (coding exon 9) of the SMPD2 gene. This alteration results from a A to G substitution at nucleotide position 826, causing the methionine (M) at amino acid position 276 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.18
Sift	Benign	0.074	T
Sift4G	Benign	0.52	T
Polyphen		0.95	P
Vest4		0.73
MutPred		0.37		Loss of disorder (P = 0.0904);
MVP		0.39
MPC		0.086
ClinPred		0.70	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr6-109764566;