11-112087971-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003002.4(SDHD):​c.167A>G​(p.His56Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense, splice_region

Scores

1
5
13
Splicing: ADA: 0.004642
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.738
Variant links:
Genes affected
SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19078213).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHDNM_003002.4 linkc.167A>G p.His56Arg missense_variant, splice_region_variant Exon 2 of 4 ENST00000375549.8 NP_002993.1 O14521-1A0A0S2Z4J3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHDENST00000375549.8 linkc.167A>G p.His56Arg missense_variant, splice_region_variant Exon 2 of 4 1 NM_003002.4 ENSP00000364699.3 O14521-1
ENSG00000255292ENST00000532699.1 linkn.167A>G splice_region_variant, non_coding_transcript_exon_variant Exon 2 of 6 3 ENSP00000456434.1 H3BRW5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443188
Hom.:
0
Cov.:
26
AF XY:
0.00000139
AC XY:
1
AN XY:
719266
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:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Uncertain:1
Feb 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1399547). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 56 of the SDHD protein (p.His56Arg). -

Mitochondrial complex 2 deficiency, nuclear type 3 Uncertain:1
Nov 13, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Jan 06, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.H56R variant (also known as c.167A>G), located in coding exon 2 of the SDHD gene, results from an A to G substitution at nucleotide position 167. The histidine at codon 56 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
12
DANN
Benign
0.74
DEOGEN2
Uncertain
0.73
D;.;.;.;.;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.083
N
LIST_S2
Benign
0.65
T;T;T;T;T;.
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.16
T;T;T;T;T;T
MetaSVM
Uncertain
0.45
D
MutationAssessor
Benign
1.9
L;L;.;L;.;L
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.2
N;.;N;D;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.27
T;.;D;D;T;T
Sift4G
Benign
0.19
T;T;T;D;T;T
Polyphen
0.0050
B;.;.;.;.;.
Vest4
0.21
MutPred
0.41
Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);
MVP
1.0
MPC
0.23
ClinPred
0.22
T
GERP RS
2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.058
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0046
dbscSNV1_RF
Benign
0.13
SpliceAI score (max)
0.13
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: rs1555186817; hg19: chr11-111958695; API