rs184654032

Positions:

• chr11-112095398-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000375549.8(SDHD):​c.*428A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 291,614 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (6 hom.)
• Consequence: SDHD ENST00000375549.8 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.241

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 11-112095398-A-G is Benign according to our data. Variant chr11-112095398-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 179088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00587 (894/152348) while in subpopulation NFE AF= 0.00814 (554/68032). AF 95% confidence interval is 0.00758. There are 3 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.*428A>G		3_prime_UTR_variant	4/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.*428A>G		3_prime_UTR_variant	4/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 895 AN: 152230 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00814

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00619 AC: 862 AN: 139266 Hom.: 6 Cov.: 0 AF XY: 0.00616 AC XY: 419 AN XY: 68040

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00790

Gnomad4 ASJ exome AF: 0.000787

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00555

Gnomad4 FIN exome AF: 0.00545

Gnomad4 NFE exome AF: 0.00781

Gnomad4 OTH exome AF: 0.00730

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152348 Hom.: 3 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74488

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00785

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00970

Gnomad4 NFE AF: 0.00814

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00974 Hom.: 2

Bravo AF: 0.00490

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 12, 2013

*428A>G in the 3' UTR of SDHD: This variant is not expected to have clinical sig nificance because it has been identified in 2.5% (3/120) of Colombian chromosome s and in 1.8% (2/110) of Puerto Rican chromosomes by the 1000 Genomes Project (d bSNP rs184654032). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2018

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.3
DANN	Benign	0.81

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: rs184654032; hg19: chr11-111966122;