Genetic Variant NM_020186.3:c.157T>C (chr7-97117880-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_020186.3(SDHAF3):c.157T>C(p.Phe53Leu) variant causes a missense change. The variant allele was found at a frequency of 0.024 in 1,614,092 control chromosomes in the GnomAD database, including 520 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.018 ( 35 hom., cov: 33)

Exomes 𝑓: 0.025 ( 485 hom. )

Consequence

SDHAF3
NM_020186.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.69

Publications

8 publications found

Variant links:

Genes affected

SDHAF3 (HGNC:21752): (succinate dehydrogenase complex assembly factor 3) Predicted to be involved in mitochondrial respiratory chain complex II assembly; regulation of gluconeogenesis; and succinate metabolic process. Predicted to be located in mitochondrial matrix. Predicted to be active in mitochondrial intermembrane space. [provided by Alliance of Genome Resources, Apr 2022]

SDHAF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008035541).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0177 (2693/152324) while in subpopulation NFE AF = 0.0262 (1781/68020). AF 95% confidence interval is 0.0252. There are 35 homozygotes in GnomAd4. There are 1306 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF3	NM_020186.3 link	c.157T>C	p.Phe53Leu	missense_variant	Exon 1 of 2	ENST00000432641.3	NP_064571.1	Q9NRP4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDHAF3	ENST00000432641.3 link	c.157T>C	p.Phe53Leu	missense_variant	Exon 1 of 2	1	NM_020186.3	ENSP00000414066.2	Q9NRP4
SDHAF3	ENST00000360382.4 link	c.157T>C	p.Phe53Leu	missense_variant	Exon 1 of 3	2		ENSP00000353548.4	F8W9V1
SDHAF3	ENST00000489852.1 link	n.180T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2696

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00497

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0262

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0202

AC:

5026

AN:

248826

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.00914

Gnomad ASJ exome

AF:

0.0236

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0261

Gnomad OTH exome

AF:

0.0190

GnomAD4 exome

AF:

0.0246

AC:

36028

AN:

1461768

Hom.:

485

Cov.:

AF XY:

0.0251

AC XY:

18232

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00364

AC:

122

AN:

33476

American (AMR)

AF:

0.0102

AC:

454

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0243

AC:

634

AN:

26120

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0295

AC:

2544

AN:

86256

European-Finnish (FIN)

AF:

0.0237

AC:

1267

AN:

53408

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0266

AC:

29542

AN:

1111932

Other (OTH)

AF:

0.0229

AC:

1384

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1917

3833

5750

7666

9583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1118

2236

3354

4472

5590

<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:

0.0177

AC:

2693

AN:

152324

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1306

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00495

AC:

206

AN:

41584

American (AMR)

AF:

0.0131

AC:

200

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0257

AC:

124

AN:

4826

European-Finnish (FIN)

AF:

0.0218

AC:

232

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0262

AC:

1781

AN:

68020

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

147

293

440

586

733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0233

Hom.:

116

Bravo

AF:

0.0163

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0280

AC:

108

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0249

AC:

214

ExAC

AF:

0.0208

AC:

2529

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0209

EpiControl

AF:

0.0220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-0.73

PhyloP100

6.7

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.076

T;T

Polyphen

0.78

P;.

Vest4

0.55

MutPred

0.91

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MPC

0.49

ClinPred

0.094

GERP RS

5.0

PromoterAI

0.055

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.51

Mutation Taster

=55/45

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over