chr5-218395-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004168.4(SDHA):c.40C>G(p.Arg14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,294,294 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SDHA
NM_004168.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.333

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38239476).

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.40C>G	p.Arg14Gly	missense	Exon 1 of 15	NP_004159.2	P31040-1
SDHA	NM_001294332.2		c.40C>G	p.Arg14Gly	missense	Exon 1 of 14	NP_001281261.1	P31040-2
SDHA	NM_001330758.2		c.40C>G	p.Arg14Gly	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.40C>G	p.Arg14Gly	missense	Exon 1 of 15	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1		n.40C>G		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
SDHA	ENST00000874235.1		c.40C>G	p.Arg14Gly	missense	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000155

AC:

AN:

1294294

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

638762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26524

American (AMR)

AF:

0.00

AC:

AN:

23256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19812

East Asian (EAS)

AF:

0.00

AC:

AN:

30796

South Asian (SAS)

AF:

0.00

AC:

AN:

63306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3630

European-Non Finnish (NFE)

AF:

0.00000192

AC:

AN:

1040934

Other (OTH)

AF:

0.00

AC:

AN:

52958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (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

0.099

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.29

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.81

PhyloP100

0.33

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.84

REVEL

Benign

0.22

Sift

Uncertain

0.022

Sift4G

Uncertain

0.057

Polyphen

0.80

Vest4

0.29

MutPred

0.55

Loss of stability (P = 0.0181)

MVP

0.62

MPC

1.3

ClinPred

0.47

GERP RS

2.8

PromoterAI

0.0095

Neutral

(source)

Varity_R

0.18

gMVP

0.49

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over