rs557114966

Variant names:

• chr9-133670608-C-A
• rs557114966
• NM_001134707.2:c.2471G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-133670608-C-A
• chr9-133670608-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001134707.2(SARDH):​c.2471G>T​(p.Arg824Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.47

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.2471G>T	p.Arg824Leu	missense_variant	Exon 19 of 21	ENST00000439388.6	NP_001128179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARDH	ENST00000439388.6	c.2471G>T	p.Arg824Leu	missense_variant	Exon 19 of 21	2	NM_001134707.2	ENSP00000403084.1
SARDH	ENST00000371872.8	c.2471G>T	p.Arg824Leu	missense_variant	Exon 19 of 21	1		ENSP00000360938.4
SARDH	ENST00000371868.5	c.755G>T	p.Arg252Leu	missense_variant	Exon 7 of 9	2		ENSP00000360934.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424022 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 704906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.7	M;.;.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D;.;D
REVEL	Pathogenic	0.89
Sift	Benign	0.13	T;D;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.87	P;P;.;P
Vest4		0.93
MutPred		0.78		Loss of MoRF binding (P = 0.0177);.;.;Loss of MoRF binding (P = 0.0177);
MVP		0.94
MPC		0.88
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs557114966; hg19: chr9-136535730;