rs751904543

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004168.4(SDHA):​c.1663+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SDHA
NM_004168.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0001985
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.563
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]

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 5-251106-G-A is Benign according to our data. Variant chr5-251106-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2452802.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHANM_004168.4 linkc.1663+3G>A splice_region_variant, intron_variant Intron 12 of 14 ENST00000264932.11 NP_004159.2 P31040-1A0A024QZ30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHAENST00000264932.11 linkc.1663+3G>A splice_region_variant, intron_variant Intron 12 of 14 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.*396+3G>A splice_region_variant, intron_variant Intron 11 of 23 ENSP00000499215.1 A0A494C1T6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458954
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725854
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33382
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44716
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26128
Gnomad4 EAS exome
AF:
0.0000252
AC:
1
AN:
39696
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86148
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53420
Gnomad4 NFE exome
AF:
0.00000180
AC:
2
AN:
1111148
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60186
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Jan 30, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1663+3G>A intronic variant results from a G to A substitution 3 nucleotides after coding exon 12 in the SDHA gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Paragangliomas 5 Benign:1
Mar 11, 2025
Myriad Genetics, Inc.
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Benign
18
DANN
Benign
0.56
Mutation Taster
=39/61
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00020
dbscSNV1_RF
Benign
0.018
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs751904543; hg19: chr5-251221; COSMIC: COSV106371269; COSMIC: COSV106371269; API