chr9-133670615-G-A

Variant names:

• chr9-133670615-G-A
• rs768116522
• NM_001134707.2:c.2464C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001134707.2(SARDH):​c.2464C>T​(p.Arg822Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 1,578,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36280406).

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.2464C>T	p.Arg822Cys	missense	Exon 19 of 21	NP_001128179.1	Q9UL12-1
	SARDH	NM_007101.4		c.2464C>T	p.Arg822Cys	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.2464C>T	p.Arg822Cys	missense	Exon 19 of 21	ENSP00000403084.1	Q9UL12-1
	SARDH	ENST00000371872.8	TSL:1	c.2464C>T	p.Arg822Cys	missense	Exon 19 of 21	ENSP00000360938.4	Q9UL12-1
	SARDH	ENST00000859366.1		c.2644C>T	p.Arg882Cys	missense	Exon 20 of 22	ENSP00000529425.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000533 AC: 10 AN: 187574 AF XY: 0.0000690

Gnomad AFR exome AF: 0.000184

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: 0.0000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000533 AC: 76 AN: 1426440 Hom.: 0 Cov.: 32 AF XY: 0.0000665 AC XY: 47 AN XY: 706362

African (AFR) AF: 0.000304 AC: 10 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 39644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37886

South Asian (SAS) AF: 0.000123 AC: 10 AN: 81574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49532

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5726

European-Non Finnish (NFE) AF: 0.0000365 AC: 40 AN: 1094752

Other (OTH) AF: 0.000186 AC: 11 AN: 59016

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74492

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000506 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.0018
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.31
MutPred		0.53		Loss of MoRF binding (P = 0.0185)
MVP		0.89
MPC		0.29
ClinPred		0.41	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.75
Mutation Taster		=87/13	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: rs768116522; hg19: chr9-136535737; COSMIC: COSV100898354; COSMIC: COSV100898354;