9-133663914-T-C

Variant names:

• chr9-133663914-T-C
• rs1217651279
• NM_001134707.2:c.2732A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001134707.2(SARDH):​c.2732A>G​(p.Asn911Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30876622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.2732A>G	p.Asn911Ser	missense_variant	Exon 21 of 21	ENST00000439388.6	NP_001128179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARDH	ENST00000439388.6	c.2732A>G	p.Asn911Ser	missense_variant	Exon 21 of 21	2	NM_001134707.2	ENSP00000403084.1
SARDH	ENST00000371872.8	c.2732A>G	p.Asn911Ser	missense_variant	Exon 21 of 21	1		ENSP00000360938.4
SARDH	ENST00000371868.5	c.1082A>G	p.Asn361Ser	missense_variant	Exon 9 of 9	2		ENSP00000360934.1
SARDH	ENST00000469828.1	n.*58A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2732A>G (p.N911S) alteration is located in exon 21 (coding exon 20) of the SARDH gene. This alteration results from a A to G substitution at nucleotide position 2732, causing the asparagine (N) at amino acid position 911 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.72
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L;.;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.74	P;P;P
Vest4		0.33
MutPred		0.33		Gain of phosphorylation at N911 (P = 0.0576);.;Gain of phosphorylation at N911 (P = 0.0576);
MVP		0.73
MPC		0.32
ClinPred		0.82	D
GERP RS		3.5
Varity_R		0.092
gMVP		0.66

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: rs1217651279; hg19: chr9-136529036;