rs535627239

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_017841.4(SDHAF2):c.320G>A(p.Arg107His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

SDHAF2
NM_017841.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 9.09

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08519992).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000526 (8/152136) while in subpopulation EAS AF = 0.000965 (5/5182). AF 95% confidence interval is 0.00038. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4 link	c.320G>A	p.Arg107His	missense_variant	Exon 3 of 4	ENST00000301761.7	NP_060311.1	Q9NX18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7 link	c.320G>A	p.Arg107His	missense_variant	Exon 3 of 4	1	NM_017841.4	ENSP00000301761.3		Q9NX18
ENSG00000256591	ENST00000541135.5 link	c.320G>A	p.Arg107His	missense_variant	Exon 3 of 5	4		ENSP00000443130.1		F5H5T6

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251478

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00223

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00111

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000580

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000562

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.0000243

AC:

AN:

1111990

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000965

AC:

0.000964878

AN:

0.000964878

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.0000947

AC:

0.0000946611

AN:

0.0000946611

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000147042

AN:

0.0000147042

Gnomad4 OTH

AF:

0.000474

AC:

0.000474383

AN:

0.000474383

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Aug 04, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 25, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Ovarian cancer

Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Paragangliomas 2

Uncertain:1

Aug 07, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;D;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.085

T;T;T;T

MetaSVM

Uncertain

0.086

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.0

D;D;.;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.012

D;D;.;.

Sift4G

Uncertain

0.022

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.78, 0.76, 0.76

MutPred

0.48

Loss of stability (P = 0.083);Loss of stability (P = 0.083);Loss of stability (P = 0.083);Loss of stability (P = 0.083);

MVP

0.79

MPC

0.79

ClinPred

0.24

GERP RS

6.2

Varity_R

0.46

gMVP

0.52

Mutation Taster

=42/58

disease causing

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

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