rs140736646

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_004168.4(SDHA):c.133G>A(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,613,408 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. A45P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:8

Conservation

PhyloP100: 2.87

Publications

7 publications found

Variant links:

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
pheochromocytoma/paraganglioma syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
mitochondrial complex II deficiency, nuclear type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
neurodegeneration with ataxia and late-onset optic atrophy
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
gastrointestinal stromal tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex II deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1GG
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SDHA links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019135922).

BP6

Variant 5-223551-G-A is Benign according to our data. Variant chr5-223551-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224947.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000578 (88/152328) while in subpopulation AMR AF = 0.0036 (55/15298). AF 95% confidence interval is 0.00284. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHA	NM_004168.4	MANE Select	c.133G>A	p.Ala45Thr	missense	Exon 2 of 15	NP_004159.2	P31040-1
SDHA	NM_001294332.2		c.133G>A	p.Ala45Thr	missense	Exon 2 of 14	NP_001281261.1	P31040-2
SDHA	NM_001330758.2		c.133G>A	p.Ala45Thr	missense	Exon 2 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SDHA	ENST00000264932.11	TSL:1 MANE Select	c.133G>A	p.Ala45Thr	missense	Exon 2 of 15	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1		n.133G>A		non_coding_transcript_exon	Exon 2 of 24	ENSP00000499215.1	A0A494C1T6
SDHA	ENST00000874235.1		c.133G>A	p.Ala45Thr	missense	Exon 2 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000426

AC:

107

AN:

251182

AF XY:

0.000471

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000855

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000350

AC:

512

AN:

1461080

Hom.:

Cov.:

AF XY:

0.000344

AC XY:

250

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.000626

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000396

AC:

440

AN:

1111304

Other (OTH)

AF:

0.000530

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000578

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41578

American (AMR)

AF:

0.00360

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68030

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000422

Hom.:

Bravo

AF:

0.00106

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Pheochromocytoma/paraganglioma syndrome 5 (3)

Hereditary cancer-predisposing syndrome (2)

Hereditary pheochromocytoma-paraganglioma (1)

Hereditary renal cell carcinoma (1)

Leigh syndrome (1)

Mitochondrial complex II deficiency, nuclear type 1 (1)

not specified (1)

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)

SDHA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

0.064

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

M_CAP

Benign

0.017

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.7

PhyloP100

2.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.1

REVEL

Benign

0.19

Sift

Benign

0.11

Sift4G

Benign

0.14

Polyphen

0.0030

Vest4

0.11

MVP

0.81

MPC

0.47

ClinPred

0.070

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.65

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over