dbSNP rs146653693: SDHA:p.Asp241Asp (chr5-228286-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_004168.4(SDHA):c.723C>T(p.Asp241Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000744 in 1,613,656 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).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

SDHA
NM_004168.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:16

Conservation

PhyloP100: -0.526

Publications

2 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 5-228286-C-T is Benign according to our data. Variant chr5-228286-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 353203.

BP7

Synonymous conserved (PhyloP=-0.526 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000447 (68/152040) while in subpopulation NFE AF = 0.000764 (52/68032). AF 95% confidence interval is 0.000598. There are 0 homozygotes in GnomAd4. There are 29 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.723C>T	p.Asp241Asp	synonymous	Exon 6 of 15	NP_004159.2	P31040-1
SDHA	NM_001294332.2		c.579C>T	p.Asp193Asp	synonymous	Exon 5 of 14	NP_001281261.1	P31040-2
SDHA	NM_001330758.2		c.723C>T	p.Asp241Asp	synonymous	Exon 6 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.723C>T	p.Asp241Asp	synonymous	Exon 6 of 15	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1		n.723C>T		non_coding_transcript_exon	Exon 6 of 24	ENSP00000499215.1	A0A494C1T6
SDHA	ENST00000874235.1		c.723C>T	p.Asp241Asp	synonymous	Exon 6 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000446

AC:

112

AN:

251188

AF XY:

0.000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000705

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000775

AC:

1133

AN:

1461616

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

544

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33470

American (AMR)

AF:

0.000380

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00130

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000936

AC:

1041

AN:

1111790

Other (OTH)

AF:

0.000480

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000447

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41390

American (AMR)

AF:

0.000262

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.000506

Hom.:

Bravo

AF:

0.000427

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Hereditary cancer-predisposing syndrome (2)

not specified (2)

Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)

Hereditary pheochromocytoma-paraganglioma (1)

Leigh syndrome (1)

Mitochondrial complex II deficiency, nuclear type 1 (1)

Pheochromocytoma/paraganglioma syndrome 5 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.3

(source)

DANN

Benign

0.40

PhyloP100

-0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over