rs142135772

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_003002.4(SDHD):​c.278A>C​(p.Tyr93Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

SDHD
NM_003002.4 missense

Scores

8
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.73
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 Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity DHSD_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_003002.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SDHDNM_003002.4 linkc.278A>C p.Tyr93Ser missense_variant 3/4 ENST00000375549.8 NP_002993.1 O14521-1A0A0S2Z4J3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SDHDENST00000375549.8 linkc.278A>C p.Tyr93Ser missense_variant 3/41 NM_003002.4 ENSP00000364699.3 O14521-1
ENSG00000255292ENST00000532699.1 linkn.278A>C non_coding_transcript_exon_variant 3/63 ENSP00000456434.1 H3BRW5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D;.;.;.;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D;D;D;.;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.8
L;L;.;.;L;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.8
D;.;D;D;D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D;.;D;D;D;T
Sift4G
Benign
0.16
T;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.81
MutPred
0.53
Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);.;
MVP
0.91
MPC
0.89
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.89
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs142135772; hg19: chr11-111959699; API