9-133666782-C-T

Variant names:

• chr9-133666782-C-T
• rs369369714
• NM_001134707.2:c.2584G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001134707.2(SARDH):​c.2584G>A​(p.Asp862Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,603,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.239

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_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03659749).
• BP6: Variant 9-133666782-C-T is Benign according to our data. Variant chr9-133666782-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2363600.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.2584G>A	p.Asp862Asn	missense_variant	Exon 20 of 21	ENST00000439388.6	NP_001128179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARDH	ENST00000439388.6	c.2584G>A	p.Asp862Asn	missense_variant	Exon 20 of 21	2	NM_001134707.2	ENSP00000403084.1
SARDH	ENST00000371872.8	c.2584G>A	p.Asp862Asn	missense_variant	Exon 20 of 21	1		ENSP00000360938.4
SARDH	ENST00000371868.5	c.934G>A	p.Asp312Asn	missense_variant	Exon 8 of 9	2		ENSP00000360934.1
SARDH	ENST00000469828.1	n.342G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 65 AN: 228914 Hom.: 0 AF XY: 0.000250 AC XY: 31 AN XY: 123864

Gnomad AFR exome AF: 0.000143

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00106

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000586

Gnomad OTH exome AF: 0.000354

GnomAD4 exome AF: 0.000152 AC: 220 AN: 1450676 Hom.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 115 AN XY: 720552

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000994

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000976

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74500

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000223 AC: 27

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.52
DEOGEN2	Benign	0.31	T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N;.;.;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.62	N;N;.;N
REVEL	Benign	0.093
Sift	Benign	0.54	T;T;.;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.0030	B;B;.;B
Vest4		0.35
MVP		0.31
MPC		0.21
ClinPred		0.00058	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.60

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: rs369369714; hg19: chr9-136531904;