Genetic Variant ENSG00000286001:n.-4dupA (chr5-218351-C-CA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000651543.1(ENSG00000286001):n.-4dupA variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

ENSG00000286001
ENST00000651543.1 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.05

Publications

0 publications found

Variant links:

Genes affected

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

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:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.-4dupA		5_prime_UTR_variant	Exon 1 of 15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30
CCDC127	NM_145265.3 link	c.-270dupT		upstream_gene_variant		ENST00000296824.4	NP_660308.1	Q96BQ5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000286001	ENST00000651543.1 link	n.-4dupA	non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1	A0A494C1T6
SDHA	ENST00000264932.11 link	c.-4dupA	5_prime_UTR_variant	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 link	n.-4dupA	5_prime_UTR_variant	Exon 1 of 24			ENSP00000499215.1	A0A494C1T6
CCDC127	ENST00000296824.4 link	c.-270dupT	upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2	Q96BQ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305910

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

644432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26848

American (AMR)

AF:

0.00

AC:

AN:

24564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20334

East Asian (EAS)

AF:

0.00

AC:

AN:

30952

South Asian (SAS)

AF:

0.00

AC:

AN:

66032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3700

European-Non Finnish (NFE)

AF:

9.56e-7

AC:

AN:

1046260

Other (OTH)

AF:

0.00

AC:

AN:

53456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Jan 04, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-4dupA variant is located in the 5' untranslated region (5'UTR) of the SDHA gene. This variant results from a duplication of an A nucleotide 4 nucleotides upstream from the first translated codon. This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.0

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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5-218351-C-CA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over