9-133670624-C-T

Position:

• chr9-133670624-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134707.2(SARDH):​c.2455G>A​(p.Ala819Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,579,404 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (70 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (63 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.714

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00187096).
• BP6: Variant 9-133670624-C-T is Benign according to our data. Variant chr9-133670624-C-T is described in ClinVar as [Benign]. Clinvar id is 776458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2150/152314) while in subpopulation AFR AF= 0.0482 (2004/41562). AF 95% confidence interval is 0.0465. There are 70 homozygotes in gnomad4. There are 963 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.2455G>A	p.Ala819Thr	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.2455G>A	p.Ala819Thr	missense_variant	19/21	2	NM_001134707.2	ENSP00000403084	P1
SARDH	ENST00000371872.8	c.2455G>A	p.Ala819Thr	missense_variant	19/21	1		ENSP00000360938	P1
SARDH	ENST00000371868.5	c.739G>A	p.Ala247Thr	missense_variant	7/9	2		ENSP00000360934

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2150 AN: 152196 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00374 AC: 704 AN: 187998 Hom.: 23 AF XY: 0.00276 AC XY: 281 AN XY: 101844

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000793

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000395

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.00160 AC: 2287 AN: 1427090 Hom.: 63 Cov.: 32 AF XY: 0.00147 AC XY: 1041 AN XY: 706752

Gnomad4 AFR exome AF: 0.0512

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.0000786

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.0141 AC: 2150 AN: 152314 Hom.: 70 Cov.: 33 AF XY: 0.0129 AC XY: 963 AN XY: 74482

Gnomad4 AFR AF: 0.0482

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00325 Hom.: 10

Bravo AF: 0.0162

ESP6500AA AF: 0.0457 AC: 197

ESP6500EA AF: 0.000706 AC: 6

ExAC AF: 0.00381 AC: 452

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	0.068
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.87
DANN	Benign	0.92
DEOGEN2	Benign	0.31	T;T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.41	.;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.080	N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.54	T;T;.;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.18
MVP		0.27
MPC		0.20
ClinPred		0.0050	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.52

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: rs61685718; hg19: chr9-136535746; COSMIC: COSV64100573; COSMIC: COSV64100573;