chr11-112089809-T-C

Variant names:

• chr11-112089809-T-C
• rs10789859
• NM_003002.4:c.314+798T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003002.4(SDHD):​c.314+798T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,054 control chromosomes in the GnomAD database, including 8,214 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8214 hom., cov: 32)
• Consequence: SDHD NM_003002.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.314+798T>C		intron_variant	Intron 3 of 3	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.314+798T>C		intron_variant	Intron 3 of 3	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.314+798T>C		intron_variant	Intron 3 of 5	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47599 AN: 151936 Hom.: 8213 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.305

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.313 AC: 47609 AN: 152054 Hom.: 8214 Cov.: 32 AF XY: 0.320 AC XY: 23807 AN XY: 74326

African (AFR) AF: 0.169 AC: 7017 AN: 41510

American (AMR) AF: 0.340 AC: 5185 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1014 AN: 3466

East Asian (EAS) AF: 0.586 AC: 3025 AN: 5164

South Asian (SAS) AF: 0.401 AC: 1935 AN: 4822

European-Finnish (FIN) AF: 0.375 AC: 3958 AN: 10544

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24219 AN: 67964

Other (OTH) AF: 0.304 AC: 641 AN: 2108

Alfa AF: 0.340 Hom.: 15295

Bravo AF: 0.307

Asia WGS AF: 0.430 AC: 1499 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.1
DANN	Benign	0.70
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10789859; hg19: chr11-111960533;