1-17028667-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_003000.3(SDHB):​c.356C>G​(p.Thr119Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T119N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SDHB
NM_003000.3 missense

Scores

2
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.14
Variant links:
Genes affected
SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_003000.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31565398).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHBNM_003000.3 linkc.356C>G p.Thr119Ser missense_variant Exon 4 of 8 ENST00000375499.8 NP_002991.2 P21912
SDHBNM_001407361.1 linkc.356C>G p.Thr119Ser missense_variant Exon 4 of 8 NP_001394290.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHBENST00000375499.8 linkc.356C>G p.Thr119Ser missense_variant Exon 4 of 8 1 NM_003000.3 ENSP00000364649.3 P21912

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.58
D;.;T
Eigen
Benign
-0.036
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.070
D
MetaRNN
Benign
0.32
T;T;T
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Benign
0.58
N;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.0
N;.;.
REVEL
Uncertain
0.39
Sift
Benign
0.36
T;.;.
Sift4G
Benign
0.74
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.096
MutPred
0.26
Loss of helix (P = 0.0376);.;.;
MVP
0.93
MPC
0.15
ClinPred
0.78
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.094
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-17355162; API