5-233550-C-T

Variant names:

• chr5-233550-C-T
• rs142849100
• NM_004168.4:c.969C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_004168.4(SDHA):​c.969C>T​(p.Gly323Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,614,066 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G323G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (83 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: -1.74
• Publications: 7 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]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 5-233550-C-T is Benign according to our data. Variant chr5-233550-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141242.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00453 (690/152224) while in subpopulation SAS AF = 0.0193 (93/4814). AF 95% confidence interval is 0.0161. There are 4 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.969C>T	p.Gly323Gly	synonymous	Exon 8 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.825C>T	p.Gly275Gly	synonymous	Exon 7 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.969C>T	p.Gly323Gly	synonymous	Exon 8 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.969C>T	p.Gly323Gly	synonymous	Exon 8 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.969C>T		non_coding_transcript_exon	Exon 8 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.969C>T	p.Gly323Gly	synonymous	Exon 8 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152106 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00579

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00724 AC: 1821 AN: 251496 AF XY: 0.00850

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00607

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00707 AC: 10329 AN: 1461842 Hom.: 83 Cov.: 32 AF XY: 0.00760 AC XY: 5524 AN XY: 727216

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00244 AC: 109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 642 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0220 AC: 1901 AN: 86254

European-Finnish (FIN) AF: 0.00168 AC: 90 AN: 53416

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5766

European-Non Finnish (NFE) AF: 0.00635 AC: 7063 AN: 1111970

Other (OTH) AF: 0.00690 AC: 417 AN: 60396

GnomAD4 genome AF: 0.00453 AC: 690 AN: 152224 Hom.: 4 Cov.: 33 AF XY: 0.00441 AC XY: 328 AN XY: 74422

African (AFR) AF: 0.00113 AC: 47 AN: 41540

American (AMR) AF: 0.00248 AC: 38 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4814

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00579 AC: 394 AN: 68016

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00545 Hom.: 1

Bravo AF: 0.00435

EpiCase AF: 0.00774

EpiControl AF: 0.00717

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Hereditary pheochromocytoma and paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	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_noAF	Benign	-0.37
CADD	Benign	8.3
DANN	Benign	0.87
PhyloP100		-1.7
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs142849100; hg19: chr5-233665; COSMIC: COSV53772676;