chr9-133670734-G-C

Variant names:

• chr9-133670734-G-C
• rs141409671
• NM_001134707.2:c.2345C>G

Variant summary

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

The NM_001134707.2(SARDH):​c.2345C>G​(p.Ala782Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,433,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. A782V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• Publications: 3 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=0.4159447).

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.2345C>G	p.Ala782Gly	missense	Exon 19 of 21	NP_001128179.1	Q9UL12-1
	SARDH	NM_007101.4		c.2345C>G	p.Ala782Gly	missense	Exon 19 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.2345C>G	p.Ala782Gly	missense	Exon 19 of 21	ENSP00000403084.1	Q9UL12-1
	SARDH	ENST00000371872.8	TSL:1	c.2345C>G	p.Ala782Gly	missense	Exon 19 of 21	ENSP00000360938.4	Q9UL12-1
	SARDH	ENST00000859366.1		c.2525C>G	p.Ala842Gly	missense	Exon 20 of 22	ENSP00000529425.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000936 AC: 2 AN: 213774 AF XY: 0.00000853

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 8 AN: 1433428 Hom.: 0 Cov.: 32 AF XY: 0.00000563 AC XY: 4 AN XY: 710896

African (AFR) AF: 0.00 AC: 0 AN: 32484

American (AMR) AF: 0.0000244 AC: 1 AN: 40990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24168

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.0000489 AC: 4 AN: 81794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099192

Other (OTH) AF: 0.00 AC: 0 AN: 59002

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ExAC AF: 0.00000836 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.55
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.83
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.47
MutPred		0.56		Gain of disorder (P = 0.0664)
MVP		0.53
MPC		0.29
ClinPred		0.093	T
GERP RS		0.80
Varity_R		0.10
gMVP		0.76
Mutation Taster		=88/12	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: rs141409671; hg19: chr9-136535856;