rs780064103

Variant names:

• chr5-218360-C-A
• rs780064103
• NM_004168.4:c.5C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-218360-C-A
• chr5-218360-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004168.4(SDHA):​c.5C>A​(p.Ser2*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S2S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.04
• Publications: 0 publications found

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]

ENSG00000286001 (HGNC:):

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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 251 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-218360-C-A is Pathogenic according to our data. Variant chr5-218360-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 644096.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.5C>A	p.Ser2*	stop_gained	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.5C>A	p.Ser2*	stop_gained	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.5C>A	p.Ser2*	stop_gained	Exon 1 of 13	NP_001317687.1	D6RFM5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.5C>A	p.Ser2*	stop_gained	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.5C>A		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.5C>A	p.Ser2*	stop_gained	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1307560 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 645524

African (AFR) AF: 0.00 AC: 0 AN: 26874

American (AMR) AF: 0.00 AC: 0 AN: 25292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20418

East Asian (EAS) AF: 0.00 AC: 0 AN: 31024

South Asian (SAS) AF: 0.00 AC: 0 AN: 66042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046826

Other (OTH) AF: 0.00 AC: 0 AN: 53498

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
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_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	0.98
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		3.0
Vest4		0.60
GERP RS		2.8
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs780064103; hg19: chr5-218475;