9-133670734-G-A

Position:

• chr9-133670734-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001134707.2(SARDH):​c.2345C>T​(p.Ala782Val) variant causes a missense change. The variant allele was found at a frequency of 0.00304 in 1,585,754 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (11 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.58

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017976671).
• BP6: Variant 9-133670734-G-A is Benign according to our data. Variant chr9-133670734-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 718828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.2345C>T	p.Ala782Val	missense_variant	19/21	ENST00000439388.6	NP_001128179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SARDH	ENST00000439388.6	c.2345C>T	p.Ala782Val	missense_variant	19/21	2	NM_001134707.2	ENSP00000403084.1
SARDH	ENST00000371872.8	c.2345C>T	p.Ala782Val	missense_variant	19/21	1		ENSP00000360938.4
SARDH	ENST00000371868.5	c.629C>T	p.Ala210Val	missense_variant	7/9	2		ENSP00000360934.1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 398 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00285 AC: 610 AN: 213774 Hom.: 3 AF XY: 0.00272 AC XY: 319 AN XY: 117200

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.00508

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.000675

Gnomad FIN exome AF: 0.0000535

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00309 AC: 4429 AN: 1433418 Hom.: 11 Cov.: 32 AF XY: 0.00298 AC XY: 2121 AN XY: 710896

Gnomad4 AFR exome AF: 0.000462

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0000763

Gnomad4 SAS exome AF: 0.000611

Gnomad4 FIN exome AF: 0.0000590

Gnomad4 NFE exome AF: 0.00329

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00209 AC XY: 156 AN XY: 74496

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00313

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00273 Hom.: 2

Bravo AF: 0.00320

ESP6500AA AF: 0.000695 AC: 3

ESP6500EA AF: 0.00294 AC: 25

ExAC AF: 0.00255 AC: 305

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SARDH: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.70
DEOGEN2	Uncertain	0.42	T;D;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	.;T;T;T
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;.;.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Benign	0.22
Sift	Benign	0.50	T;T;.;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.34	B;B;.;B
Vest4		0.43
MVP		0.56
MPC		0.58
ClinPred		0.062	T
GERP RS		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.84

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: rs141409671; hg19: chr9-136535856;