rs144867876

Positions:

chr11-61437685-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017841.4(SDHAF2):c.97C>T(p.Arg33Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SDHAF2
NM_017841.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 0.884

Variant links:

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]

SDHAF2 links:

ENSG00000256591 (HGNC:):

ENSG00000256591 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049116015).

BP6

Variant 11-61437685-C-T is Benign according to our data. Variant chr11-61437685-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 41837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61437685-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000341 (52/152328) while in subpopulation EAS AF= 0.00675 (35/5184). AF 95% confidence interval is 0.00499. There are 1 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHAF2	NM_017841.4 linkuse as main transcript	c.97C>T	p.Arg33Cys	missense_variant	2/4	ENST00000301761.7	NP_060311.1	Q9NX18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7 linkuse as main transcript	c.97C>T	p.Arg33Cys	missense_variant	2/4	1	NM_017841.4	ENSP00000301761.3		Q9NX18
ENSG00000256591	ENST00000541135.5 linkuse as main transcript	c.97C>T	p.Arg33Cys	missense_variant	2/5	4		ENSP00000443130.1		F5H5T6

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000525

AC:

132

AN:

251470

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00609

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

205

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00272

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000341

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00675

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000519

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SDHAF2: BP4, BS1 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 02, 2017	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 31, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2018	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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.038

.;T;.;.;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

T;T;T;T;T

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.5

.;L;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.99

N;N;.;.;N

REVEL

Benign

0.24

Sift

Benign

0.098

T;T;.;.;T

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.047

.;B;.;.;.

Vest4

0.31, 0.30, 0.35, 0.31

MVP

0.64

MPC

0.26

ClinPred

0.044

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.068

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over