rs142135772

Positions:

• chr11-112088975-A-C
• chr11-112088975-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73

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]

ENSG00000255292 (HGNC:):

ACMG classification

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
SDHD	NM_003002.4	c.278A>C	p.Tyr93Ser	missense_variant	3/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.278A>C	p.Tyr93Ser	missense_variant	3/4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.278A>C		non_coding_transcript_exon_variant	3/6	3		ENSP00000456434.1

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

Other links and lift over

dbSNP: rs142135772; hg19: chr11-111959699;