chr5-218347-A-G

Variant names:

• chr5-218347-A-G
• rs771470290
• ENST00000651543.1:n.-9A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000651543.1(ENSG00000286001):​n.-9A>G 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 0.0000365 in 1,451,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ENSG00000286001 ENST00000651543.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.406
• Publications: 0 publications found

Genes affected

ENSG00000286001 (HGNC:):

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.-9A>G		5_prime_UTR_variant	Exon 1 of 15	ENST00000264932.11	NP_004159.2
CCDC127	NM_145265.3	c.-265T>C		upstream_gene_variant		ENST00000296824.4	NP_660308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286001	ENST00000651543.1	n.-9A>G		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1
SDHA	ENST00000264932.11	c.-9A>G		5_prime_UTR_variant	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.-9A>G		5_prime_UTR_variant	Exon 1 of 24			ENSP00000499215.1
CCDC127	ENST00000296824.4	c.-265T>C		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000190 AC: 2 AN: 105172 AF XY: 0.0000329

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 48 AN: 1299538 Hom.: 0 Cov.: 31 AF XY: 0.0000312 AC XY: 20 AN XY: 640678

African (AFR) AF: 0.0000751 AC: 2 AN: 26638

American (AMR) AF: 0.0000427 AC: 1 AN: 23428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20062

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30830

South Asian (SAS) AF: 0.00 AC: 0 AN: 65110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3686

European-Non Finnish (NFE) AF: 0.0000383 AC: 40 AN: 1043144

Other (OTH) AF: 0.0000753 AC: 4 AN: 53130

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152170 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

African (AFR) AF: 0.0000965 AC: 4 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 02, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHA c.-9A>G variant has not been reported in individuals with SDHA-related conditions in the published literature. The frequency of this variant in the general population, 0.000022 (3/136500 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.4
DANN	Benign	0.26
PhyloP100		-0.41
PromoterAI		0.087	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs771470290; hg19: chr5-218462;