9-133666809-G-A

Variant summary

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

The NM_001134707.2(SARDH):​c.2557C>T​(p.Arg853Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,200 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: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SARDH
NM_001134707.2 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.51
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]

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, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SARDHNM_001134707.2 linkc.2557C>T p.Arg853Trp missense_variant Exon 20 of 21 ENST00000439388.6 NP_001128179.1 Q9UL12-1A8K596

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SARDHENST00000439388.6 linkc.2557C>T p.Arg853Trp missense_variant Exon 20 of 21 2 NM_001134707.2 ENSP00000403084.1 Q9UL12-1
SARDHENST00000371872.8 linkc.2557C>T p.Arg853Trp missense_variant Exon 20 of 21 1 ENSP00000360938.4 Q9UL12-1
SARDHENST00000371868.5 linkc.907C>T p.Arg303Trp missense_variant Exon 8 of 9 2 ENSP00000360934.1 Q5SYV2
SARDHENST00000469828.1 linkn.315C>T non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1456200
Hom.:
0
Cov.:
32
AF XY:
0.00000414
AC XY:
3
AN XY:
723826
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000451
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2557C>T (p.R853W) alteration is located in exon 20 (coding exon 19) of the SARDH gene. This alteration results from a C to T substitution at nucleotide position 2557, causing the arginine (R) at amino acid position 853 to be replaced by a tryptophan (W). 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
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.75
D;D;.;D
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
.;D;D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Pathogenic
3.3
M;.;.;M
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-6.8
D;D;.;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.98
MutPred
0.72
Loss of MoRF binding (P = 0.1258);.;.;Loss of MoRF binding (P = 0.1258);
MVP
0.91
MPC
0.81
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.69
gMVP
0.95

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.

Other links and lift over

dbSNP: rs1198774607; hg19: chr9-136531931; COSMIC: COSV64100540; API