Variant 9-133671601-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001134707.2(SARDH):c.2260G>A(p.Ala754Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,604,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SARDH
NM_001134707.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.36

Variant links:

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 links:

SARDH (HGNC:):

SARDH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SARDH	NM_001134707.2 linkuse as main transcript	c.2260G>A	p.Ala754Thr	missense_variant	18/21	ENST00000439388.6	NP_001128179.1	Q9UL12-1A8K596

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SARDH	ENST00000439388.6 linkuse as main transcript	c.2260G>A	p.Ala754Thr	missense_variant	18/21	2	NM_001134707.2	ENSP00000403084.1	Q9UL12-1
SARDH	ENST00000371872.8 linkuse as main transcript	c.2260G>A	p.Ala754Thr	missense_variant	18/21	1		ENSP00000360938.4	Q9UL12-1
SARDH	ENST00000371868.5 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant	6/9	2		ENSP00000360934.1	Q5SYV2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000215

AC:

AN:

232392

Hom.:

AF XY:

0.0000238

AC XY:

AN XY:

126114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000302

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:

0.0000384

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000399

AC:

AN:

1452716

Hom.:

Cov.:

AF XY:

0.0000346

AC XY:

AN XY:

721850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000487

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

The c.2260G>A (p.A754T) alteration is located in exon 18 (coding exon 17) of the SARDH gene. This alteration results from a G to A substitution at nucleotide position 2260, causing the alanine (A) at amino acid position 754 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

0.090

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D;.;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.9

M;.;.;M

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

N;D;.;N

REVEL

Pathogenic

0.66

Sift

Benign

0.056

T;D;.;T

Sift4G

Benign

0.095

T;D;T;T

Polyphen

0.99

D;P;.;D

Vest4

0.63

MutPred

0.87

Gain of methylation at K757 (P = 0.0858);.;.;Gain of methylation at K757 (P = 0.0858);

MVP

0.84

MPC

0.34

ClinPred

0.80

GERP RS

5.0

Varity_R

0.26

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over