rs755475561

chr11-112089028-CA-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_003002.4(SDHD):c.314+20del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: SDHD NM_003002.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.626

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 11-112089028-CA-C is Benign according to our data. Variant chr11-112089028-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258892.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000746 (109/1461546) while in subpopulation MID AF= 0.00052 (3/5764). AF 95% confidence interval is 0.000314. There are 0 homozygotes in gnomad4_exome. There are 50 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.314+20del		intron_variant		ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.314+20del		intron_variant		1	NM_003002.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251452 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461546 Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2014

The c.314+20delA alteration is located in Intron 3 (E) of the SDHD gene. This alteration consists of a deletion of 1 nucleotides at nucleotide position c.31420 Intron 3 (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs755475561; hg19: chr11-111959752;