chr5-218353-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000651543.1(ENSG00000286001):​n.-3G>T 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 0.00000459 in 1,306,702 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: not found (cov: 34)
Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

ENSG00000286001
ENST00000651543.1 non_coding_transcript_exon

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.0690

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=-0.78).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHANM_004168.4 linkc.-3G>T 5_prime_UTR_variant Exon 1 of 15 ENST00000264932.11 NP_004159.2 P31040-1A0A024QZ30
CCDC127NM_145265.3 linkc.-271C>A upstream_gene_variant ENST00000296824.4 NP_660308.1 Q96BQ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENSG00000286001ENST00000651543.1 linkn.-3G>T non_coding_transcript_exon_variant Exon 1 of 24 ENSP00000499215.1 A0A494C1T6
SDHAENST00000264932.11 linkc.-3G>T 5_prime_UTR_variant Exon 1 of 15 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.-3G>T 5_prime_UTR_variant Exon 1 of 24 ENSP00000499215.1 A0A494C1T6
CCDC127ENST00000296824.4 linkc.-271C>A upstream_gene_variant 1 NM_145265.3 ENSP00000296824.2 Q96BQ5

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000459
AC:
6
AN:
1306702
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
644858
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26842
American (AMR)
AF:
0.00
AC:
0
AN:
24642
Ashkenazi Jewish (ASJ)
AF:
0.0000491
AC:
1
AN:
20378
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30986
South Asian (SAS)
AF:
0.00
AC:
0
AN:
66078
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33898
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3696
European-Non Finnish (NFE)
AF:
0.00000478
AC:
5
AN:
1046714
Other (OTH)
AF:
0.00
AC:
0
AN:
53468
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 11, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1
May 20, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.-3G>T variant is located in the 5' untranslated region (5&rsquo; UTR) of the SDHA gene. This variant results from a G to T substitution 3 bases upstream from the first translated codon. This nucleotide position is well conserved on limited sequence alignment. 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
BayesDel_noAF
Benign
-0.78
CADD
Benign
7.9
DANN
Benign
0.70
PhyloP100
0.069
PromoterAI
-0.30
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=299/1
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

Publications

Other links and lift over

dbSNP: rs1553996340; hg19: chr5-218468; API