9-133666782-C-G

Variant names:

• chr9-133666782-C-G
• rs369369714
• NM_001134707.2:c.2584G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134707.2(SARDH):​c.2584G>C​(p.Asp862His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D862N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239
• Publications: 2 publications found

Genes affected

SARDH (HGNC:10536): (sarcosine dehydrogenase) This gene encodes an enzyme localized to the mitochondrial matrix which catalyzes the oxidative demethylation of sarcosine. This enzyme is distinct from another mitochondrial matrix enzyme, dimethylglycine dehydrogenase, which catalyzes a reaction resulting in the formation of sarcosine. Mutations in this gene are associated with sarcosinemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2008]

SARDH Gene-Disease associations (from GenCC):

• sarcosinemia

  Inheritance: AR, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38088202).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134707.2. 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
	SARDH	NM_001134707.2	MANE Select	c.2584G>C	p.Asp862His	missense	Exon 20 of 21	NP_001128179.1	Q9UL12-1
	SARDH	NM_007101.4		c.2584G>C	p.Asp862His	missense	Exon 20 of 21	NP_009032.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SARDH	ENST00000439388.6	TSL:2 MANE Select	c.2584G>C	p.Asp862His	missense	Exon 20 of 21	ENSP00000403084.1	Q9UL12-1
	SARDH	ENST00000371872.8	TSL:1	c.2584G>C	p.Asp862His	missense	Exon 20 of 21	ENSP00000360938.4	Q9UL12-1
	SARDH	ENST00000859366.1		c.2764G>C	p.Asp922His	missense	Exon 21 of 22	ENSP00000529425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228914 AF XY: 0.00000807

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450676 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720552

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.00 AC: 0 AN: 43082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 39236

South Asian (SAS) AF: 0.00 AC: 0 AN: 84218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107104

Other (OTH) AF: 0.00 AC: 0 AN: 60002

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.24
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.41
Sift	Benign	0.049	D
Sift4G	Uncertain	0.030	D
Polyphen		0.81	P
Vest4		0.44
MutPred		0.53		Gain of MoRF binding (P = 0.0711)
MVP		0.60
MPC		0.30
ClinPred		0.15	T
GERP RS		-1.5
Varity_R		0.068
gMVP		0.78
Mutation Taster		=86/14	polymorphism

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: rs369369714; hg19: chr9-136531904;