rs201472512

Variant names:

• chr11-112095792-T-C
• rs201472512
• NM_003002.4:c.*822T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003002.4(SDHD):​c.*822T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 200,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: SDHD NM_003002.4 splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.508

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00126 (192/152280) while in subpopulation NFE AF= 0.00212 (144/68026). AF 95% confidence interval is 0.00183. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.*822T>C		splice_region_variant	Exon 4 of 4	ENST00000375549.8	NP_002993.1
SDHD	NM_003002.4	c.*822T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.*822T>C		splice_region_variant	Exon 4 of 4	1	NM_003002.4	ENSP00000364699.3
SDHD	ENST00000375549.8	c.*822T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.314+6781T>C		intron_variant	Intron 3 of 5	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00111 AC: 53 AN: 47952 Hom.: 0 Cov.: 0 AF XY: 0.000804 AC XY: 18 AN XY: 22400

Gnomad4 AFR exome AF: 0.000480

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00221

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74474

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00274

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00365 Hom.: 0

Bravo AF: 0.000824

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 14, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The *822T>C variant in SDHD has not been previously reported in individuals with pheochromocytomas or paragangliomas. Data from large population studies is insu fficient to estimate its frequency, though it has been listed in dbSNP without f requency information (rs201472512). This variant is located in the 3' untranslat ed region (3' UTR). While this region may contain important regulatory sequences , no pathogenic variants in the SDHD gene have been reported in this region. Add itional information is needed to fully assess the clinical significance of this variant. -

Pheochromocytoma Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs201472512; hg19: chr11-111966516;