9-133694267-C-T

Variant names:

• chr9-133694267-C-T
• rs762590871
• NM_001134707.2:c.1912G>A

Variant summary

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

The NM_001134707.2(SARDH):​c.1912G>A​(p.Ala638Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,548,352 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SARDH NM_001134707.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0170

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023586571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARDH	NM_001134707.2	c.1912G>A	p.Ala638Thr	missense_variant	Exon 15 of 21	ENST00000439388.6	NP_001128179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARDH	ENST00000439388.6	c.1912G>A	p.Ala638Thr	missense_variant	Exon 15 of 21	2	NM_001134707.2	ENSP00000403084.1
SARDH	ENST00000371872.8	c.1912G>A	p.Ala638Thr	missense_variant	Exon 15 of 21	1		ENSP00000360938.4
SARDH	ENST00000371868.5	c.196G>A	p.Ala66Thr	missense_variant	Exon 3 of 9	2		ENSP00000360934.1
SARDH	ENST00000427237.6	c.*87G>A		downstream_gene_variant		2		ENSP00000394210.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000259 AC: 4 AN: 154716 Hom.: 0 AF XY: 0.0000368 AC XY: 3 AN XY: 81624

Gnomad AFR exome AF: 0.000117

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.0000136 AC: 19 AN: 1396080 Hom.: 0 Cov.: 30 AF XY: 0.0000145 AC XY: 10 AN XY: 688694

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.0000281

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: 0.0000111

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74464

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000162 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1912G>A (p.A638T) alteration is located in exon 15 (coding exon 14) of the SARDH gene. This alteration results from a G to A substitution at nucleotide position 1912, causing the alanine (A) at amino acid position 638 to be replaced by a threonine (T). 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	0.073
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;T;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L;.;.;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.70	N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.58	T;T;.;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.0090	B;B;.;B
Vest4		0.054
MutPred		0.65		Gain of glycosylation at A638 (P = 0.0106);.;.;Gain of glycosylation at A638 (P = 0.0106);
MVP		0.68
MPC		0.20
ClinPred		0.025	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.049
gMVP		0.32

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: rs762590871; hg19: chr9-136559389; COSMIC: COSV64098610; COSMIC: COSV64098610;