dbSNP rs11557098: SDHA:p.Val637Val (chr5-256336-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004168.4(SDHA):c.1911C>T(p.Val637Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,612,834 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 7 hom., cov: 34)

Exomes 𝑓: 0.0015 ( 36 hom. )

Consequence

SDHA
NM_004168.4 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.109

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031520724).

BP6

Variant 5-256336-C-T is Benign according to our data. Variant chr5-256336-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.109 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00237 (361/152338) while in subpopulation EAS AF = 0.0517 (268/5186). AF 95% confidence interval is 0.0466. There are 7 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

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.1911C>T	p.Val637Val	splice_region synonymous	Exon 15 of 15	NP_004159.2	P31040-1
SDHA	NM_001294332.2		c.1767C>T	p.Val589Val	splice_region synonymous	Exon 14 of 14	NP_001281261.1	P31040-2
SDHA	NM_001330758.2		c.1668C>T	p.Val556Val	splice_region synonymous	Exon 13 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.1911C>T	p.Val637Val	splice_region synonymous	Exon 15 of 15	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1		n.*644C>T		splice_region non_coding_transcript_exon	Exon 14 of 24	ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1		n.*644C>T		3_prime_UTR	Exon 14 of 24	ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

363

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0519

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00491

AC:

1233

AN:

251176

AF XY:

0.00437

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0565

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000476

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00151

AC:

2210

AN:

1460496

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1100

AN XY:

726708

show subpopulations

African (AFR)

AF:

0.000419

AC:

AN:

33390

American (AMR)

AF:

0.000291

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00253

AC:

AN:

26114

East Asian (EAS)

AF:

0.0370

AC:

1467

AN:

39670

South Asian (SAS)

AF:

0.00254

AC:

219

AN:

86214

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000185

AC:

206

AN:

1110888

Other (OTH)

AF:

0.00346

AC:

209

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

119

238

356

475

594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00237

AC:

361

AN:

152338

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41580

American (AMR)

AF:

0.000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.0517

AC:

268

AN:

5186

South Asian (SAS)

AF:

0.00310

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68042

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000754

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00469

AC:

569

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Pheochromocytoma/paraganglioma syndrome 5 (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 cancer-predisposing syndrome (1)

Hereditary pheochromocytoma and paraganglioma (1)

Leigh syndrome (1)

Mitochondrial complex II deficiency, nuclear type 1 (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

0.17

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.020

CADD

Benign

9.9

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.40

PhyloP100

0.11

PROVEAN

Benign

0.16

REVEL

Benign

0.14

Sift

Pathogenic

0.0

MVP

0.91

ClinPred

0.0093

GERP RS

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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