rs9919624

Positions:

• chr11-112088838-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003002.4(SDHD):​c.170-29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,611,516 control chromosomes in the GnomAD database, including 5,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2532 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2508 hom.)
• Consequence: SDHD NM_003002.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-112088838-A-G is Benign according to our data. Variant chr11-112088838-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 440261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088838-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.170-29A>G		intron_variant		ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.170-29A>G		intron_variant		1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.170-29A>G		intron_variant		3		ENSP00000456434.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16101 AN: 152114 Hom.: 2501 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0817

GnomAD3 exomes AF: 0.0341 AC: 8552 AN: 251018 Hom.: 1048 AF XY: 0.0272 AC XY: 3687 AN XY: 135666

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.0247

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00190

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0193 AC: 28183 AN: 1459284 Hom.: 2508 Cov.: 31 AF XY: 0.0179 AC XY: 12978 AN XY: 726000

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.00451

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0338

GnomAD4 genome AF: 0.106 AC: 16174 AN: 152232 Hom.: 2532 Cov.: 32 AF XY: 0.103 AC XY: 7687 AN XY: 74444

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.0496

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.0809

Alfa AF: 0.0367 Hom.: 301

Bravo AF: 0.121

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 10, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Paragangliomas 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Mitochondrial complex 2 deficiency, nuclear type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Paragangliomas 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9919624; hg19: chr11-111959562;