chr9-133694338-C-T

Variant names:

• chr9-133694338-C-T
• rs2073817
• NM_001134707.2:c.1841G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001134707.2(SARDH):​c.1841G>A​(p.Arg614His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,549,820 control chromosomes in the GnomAD database, including 106,118 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.36 (9977 hom., cov: 32)
  • Exomes 𝑓: 0.37 (96141 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.537
• Publications: 37 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059126914).
• BP6: Variant 9-133694338-C-T is Benign according to our data. Variant chr9-133694338-C-T is described in ClinVar as Benign. ClinVar VariationId is 3059588.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

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.1841G>A	p.Arg614His	missense	Exon 15 of 21	NP_001128179.1	Q9UL12-1
	SARDH	NM_007101.4		c.1841G>A	p.Arg614His	missense	Exon 15 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.1841G>A	p.Arg614His	missense	Exon 15 of 21	ENSP00000403084.1	Q9UL12-1
	SARDH	ENST00000371872.8	TSL:1	c.1841G>A	p.Arg614His	missense	Exon 15 of 21	ENSP00000360938.4	Q9UL12-1
	SARDH	ENST00000859366.1		c.1841G>A	p.Arg614His	missense	Exon 15 of 22	ENSP00000529425.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54381 AN: 151820 Hom.: 9966 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.361

GnomAD2 exomes AF: 0.378 AC: 58852 AN: 155762 AF XY: 0.371

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.458

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.416

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.369 AC: 516392 AN: 1397882 Hom.: 96141 Cov.: 41 AF XY: 0.368 AC XY: 254029 AN XY: 689462

African (AFR) AF: 0.297 AC: 9388 AN: 31582

American (AMR) AF: 0.458 AC: 16334 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8418 AN: 25166

East Asian (EAS) AF: 0.393 AC: 14046 AN: 35726

South Asian (SAS) AF: 0.325 AC: 25723 AN: 79216

European-Finnish (FIN) AF: 0.359 AC: 17350 AN: 48358

Middle Eastern (MID) AF: 0.415 AC: 2357 AN: 5678

European-Non Finnish (NFE) AF: 0.372 AC: 401490 AN: 1078514

Other (OTH) AF: 0.367 AC: 21286 AN: 57964

GnomAD4 genome AF: 0.358 AC: 54415 AN: 151938 Hom.: 9977 Cov.: 32 AF XY: 0.357 AC XY: 26480 AN XY: 74258

African (AFR) AF: 0.299 AC: 12391 AN: 41454

American (AMR) AF: 0.395 AC: 6041 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3468

East Asian (EAS) AF: 0.395 AC: 2037 AN: 5152

South Asian (SAS) AF: 0.325 AC: 1555 AN: 4788

European-Finnish (FIN) AF: 0.369 AC: 3888 AN: 10550

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25920 AN: 67938

Other (OTH) AF: 0.356 AC: 749 AN: 2102

Alfa AF: 0.373 Hom.: 42573

Bravo AF: 0.361

TwinsUK AF: 0.365 AC: 1352

ALSPAC AF: 0.366 AC: 1412

ESP6500AA AF: 0.274 AC: 1056

ESP6500EA AF: 0.345 AC: 2560

ExAC AF: 0.253 AC: 10441

Asia WGS AF: 0.366 AC: 1272 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SARDH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.54
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.077	T
Sift4G	Benign	0.16	T
Polyphen		0.98	D
Vest4		0.039
MPC		0.26
ClinPred		0.0065	T
GERP RS		2.7
Varity_R		0.076
gMVP		0.57
Mutation Taster		=98/2	polymorphism (auto)

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: rs2073817; hg19: chr9-136559460; COSMIC: COSV64099558; COSMIC: COSV64099558;