rs778202647

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003002.4(SDHD):c.13T>A(p.Trp5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SDHD
NM_003002.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0140

Publications

0 publications found

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]

SDHD links:

ENSG00000255292 (HGNC:):

ENSG00000255292 links:

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

TIMM8B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2689289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4 link	c.13T>A	p.Trp5Arg	missense_variant	Exon 1 of 4	ENST00000375549.8	NP_002993.1	O14521-1A0A0S2Z4J3
TIMM8B	NM_012459.4 link	c.-197A>T		upstream_gene_variant		ENST00000504148.3	NP_036591.3	Q9Y5J9G3XAN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDHD	ENST00000375549.8 link	c.13T>A	p.Trp5Arg	missense_variant	Exon 1 of 4	1	NM_003002.4	ENSP00000364699.3	O14521-1
ENSG00000255292	ENST00000532699.1 link	n.13T>A		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000456434.1	H3BRW5
TIMM8B	ENST00000504148.3 link	c.-197A>T		upstream_gene_variant		1	NM_012459.4	ENSP00000422122.2	Q9Y5J9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

GnomAD4 genome

Cov.:

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

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. ClinVar contains an entry for this variant (Variation ID: 1771773). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 5 of the SDHD protein (p.Trp5Arg). -

not provided

Uncertain:1

Jul 07, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 18, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W5R variant (also known as c.13T>A), located in coding exon 1 of the SDHD gene, results from a T to A substitution at nucleotide position 13. The tryptophan at codon 5 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. 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

0.18

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.30

T;.;.;.;.;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.17

T;T;T;T;T;.;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.27

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.078

MutationAssessor

Benign

1.6

L;L;.;L;.;L;L

PhyloP100

0.014

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.080

N;.;N;D;N;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.39

T;.;T;T;T;T;D

Sift4G

Benign

0.16

T;T;T;T;T;T;D

Polyphen

0.0

B;.;.;.;.;.;.

Vest4

0.45

MutPred

0.55

Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);

MVP

0.99

MPC

0.33

ClinPred

0.15

GERP RS

1.4

PromoterAI

-0.0085

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.8

Varity_R

0.14

gMVP

0.56

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over