rs113652589

Positions:

• chr11-61446083-C-T

Variant summary

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

The NM_017841.4(SDHAF2):​c.*12C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 1,614,080 control chromosomes in the GnomAD database, including 62 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 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (61 hom.)
• Consequence: SDHAF2 NM_017841.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: -0.734

Genes affected

SDHAF2 (HGNC:26034): (succinate dehydrogenase complex assembly factor 2) This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma. [provided by RefSeq, May 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-61446083-C-T is Benign according to our data. Variant chr11-61446083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61446083-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00592 (902/152318) while in subpopulation NFE AF= 0.0101 (684/68036). AF 95% confidence interval is 0.00943. There are 1 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 902 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.*12C>T		3_prime_UTR_variant	4/4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.*12C>T		3_prime_UTR_variant	4/4	1	NM_017841.4	ENSP00000301761	P1

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 901 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00511 AC: 1284 AN: 251416 Hom.: 13 AF XY: 0.00519 AC XY: 705 AN XY: 135894

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00938

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00783 AC: 11450 AN: 1461762 Hom.: 61 Cov.: 31 AF XY: 0.00756 AC XY: 5494 AN XY: 727198

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.00957

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00592 AC: 902 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.00513 AC XY: 382 AN XY: 74488

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00745 Hom.: 0

Bravo AF: 0.00603

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary pheochromocytoma-paraganglioma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 30, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.60

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: rs113652589; hg19: chr11-61213555;