NM_001134707.2:c.1785C>G

Variant names:

• chr9-133696245-G-C
• rs2502740
• NM_001134707.2:c.1785C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001134707.2(SARDH):​c.1785C>G​(p.Ser595Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,613,854 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S595S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (40 hom.)
• Consequence: SARDH NM_001134707.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.51
• Publications: 15 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-133696245-G-C is Benign according to our data. Variant chr9-133696245-G-C is described in ClinVar as Benign. ClinVar VariationId is 785297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1630/152086) while in subpopulation AFR AF = 0.0375 (1556/41474). AF 95% confidence interval is 0.036. There are 34 homozygotes in GnomAd4. There are 733 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,Unknown gene

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.1785C>G	p.Ser595Ser	synonymous	Exon 14 of 21	NP_001128179.1	Q9UL12-1
	SARDH	NM_007101.4		c.1785C>G	p.Ser595Ser	synonymous	Exon 14 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.1785C>G	p.Ser595Ser	synonymous	Exon 14 of 21	ENSP00000403084.1	Q9UL12-1
	SARDH	ENST00000371872.8	TSL:1	c.1785C>G	p.Ser595Ser	synonymous	Exon 14 of 21	ENSP00000360938.4	Q9UL12-1
	SARDH	ENST00000859366.1		c.1785C>G	p.Ser595Ser	synonymous	Exon 14 of 22	ENSP00000529425.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1629 AN: 151968 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00672

GnomAD2 exomes AF: 0.00300 AC: 754 AN: 251106 AF XY: 0.00203

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00114 AC: 1669 AN: 1461768 Hom.: 40 Cov.: 51 AF XY: 0.000938 AC XY: 682 AN XY: 727196

African (AFR) AF: 0.0417 AC: 1395 AN: 33480

American (AMR) AF: 0.00288 AC: 129 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111994

Other (OTH) AF: 0.00202 AC: 122 AN: 60394

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152086 Hom.: 34 Cov.: 32 AF XY: 0.00986 AC XY: 733 AN XY: 74334

African (AFR) AF: 0.0375 AC: 1556 AN: 41474

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67966

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.0000240 Hom.: 14750

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.010
DANN	Benign	0.32
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs2502740; hg19: chr9-136561367;