NM_004168.4:c.-7A>C

Variant names:

Variant summary

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

The NM_004168.4(SDHA):c.-7A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,455,416 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00078 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

SDHA
NM_004168.4 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:12

Conservation

PhyloP100: 0.187

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 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 5-218349-A-C is Benign according to our data. Variant chr5-218349-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 371942.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000782 (119/152270) while in subpopulation NFE AF = 0.00118 (80/67998). AF 95% confidence interval is 0.000968. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 34. 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	Effect	Exon Rank	Protein	UniProt
SDHA	NM_004168.4	MANE Select	c.-7A>C	5_prime_UTR	Exon 1 of 15	NP_004159.2	P31040-1
SDHA	NM_001294332.2		c.-7A>C	5_prime_UTR	Exon 1 of 14	NP_001281261.1	P31040-2
SDHA	NM_001330758.2		c.-7A>C	5_prime_UTR	Exon 1 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SDHA	ENST00000264932.11	TSL:1 MANE Select	c.-7A>C	5_prime_UTR	Exon 1 of 15	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1		n.-7A>C	non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
ENSG00000286001	ENST00000651543.1		n.-7A>C	5_prime_UTR	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes

AF:

0.000789

AC:

120

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000666

AC:

AN:

108066

AF XY:

0.000800

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000280

Gnomad ASJ exome

AF:

0.00185

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000169

Gnomad NFE exome

AF:

0.000793

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00103

AC:

1341

AN:

1303146

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

673

AN XY:

642938

show subpopulations

African (AFR)

AF:

0.0000374

AC:

AN:

26718

American (AMR)

AF:

0.000460

AC:

AN:

23896

Ashkenazi Jewish (ASJ)

AF:

0.00382

AC:

AN:

20162

East Asian (EAS)

AF:

0.00

AC:

AN:

30934

South Asian (SAS)

AF:

0.00102

AC:

AN:

65546

European-Finnish (FIN)

AF:

0.0000594

AC:

AN:

33658

Middle Eastern (MID)

AF:

0.00460

AC:

AN:

3694

European-Non Finnish (NFE)

AF:

0.00105

AC:

1097

AN:

1045236

Other (OTH)

AF:

0.00129

AC:

AN:

53302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000782

AC:

119

AN:

152270

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41562

American (AMR)

AF:

0.000784

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

67998

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000530

Hom.:

Bravo

AF:

0.000824

Asia WGS

AF:

0.000290

AC:

AN:

3466

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Hereditary cancer-predisposing syndrome (2)

Hereditary pheochromocytoma-paraganglioma (2)

Pheochromocytoma/paraganglioma syndrome 5 (2)

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.2

(source)

DANN

Benign

0.32

PhyloP100

0.19

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=47/253

disease causing

(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