Genetic Variant NM_004168.4:c.17G>A (chr5-218372-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004168.4(SDHA):c.17G>A(p.Gly6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,457,028 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. G6R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 5 hom., cov: 34)

Exomes 𝑓: 0.00051 ( 6 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -2.08

Publications

6 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 links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CCDC127 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030815005).

BP6

Variant 5-218372-G-A is Benign according to our data. Variant chr5-218372-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224952.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00543 (827/152286) while in subpopulation AFR AF = 0.0189 (786/41568). AF 95% confidence interval is 0.0178. There are 5 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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.17G>A	p.Gly6Asp	missense	Exon 1 of 15	NP_004159.2	P31040-1
SDHA	NM_001294332.2		c.17G>A	p.Gly6Asp	missense	Exon 1 of 14	NP_001281261.1	P31040-2
SDHA	NM_001330758.2		c.17G>A	p.Gly6Asp	missense	Exon 1 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.17G>A	p.Gly6Asp	missense	Exon 1 of 15	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1		n.17G>A		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
SDHA	ENST00000874235.1		c.17G>A	p.Gly6Asp	missense	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

826

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00137

AC:

152

AN:

110996

AF XY:

0.000825

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00174

GnomAD4 exome

AF:

0.000510

AC:

665

AN:

1304742

Hom.:

Cov.:

AF XY:

0.000419

AC XY:

270

AN XY:

644202

show subpopulations

African (AFR)

AF:

0.0185

AC:

495

AN:

26812

American (AMR)

AF:

0.00148

AC:

AN:

24940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20288

East Asian (EAS)

AF:

0.00

AC:

AN:

31056

South Asian (SAS)

AF:

0.0000612

AC:

AN:

65358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33764

Middle Eastern (MID)

AF:

0.00164

AC:

AN:

3668

European-Non Finnish (NFE)

AF:

0.0000411

AC:

AN:

1045446

Other (OTH)

AF:

0.00150

AC:

AN:

53410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00543

AC:

827

AN:

152286

Hom.:

Cov.:

AF XY:

0.00528

AC XY:

393

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0189

AC:

786

AN:

41568

American (AMR)

AF:

0.00196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68000

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

124

166

207

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:

0.0000698

Hom.:

Bravo

AF:

0.00654

ESP6500AA

AF:

0.0178

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00144

AC:

161

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (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-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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.87

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.23

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-2.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.14

REVEL

Benign

0.025

Sift

Benign

0.31

Sift4G

Benign

0.56

Polyphen

0.0040

Vest4

0.20

MVP

0.20

MPC

0.64

ClinPred

0.0022

GERP RS

-1.9

PromoterAI

-0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.78

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