5-233619-C-G

Variant names:

• chr5-233619-C-G
• rs1041949
• NM_004168.4:c.1038C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004168.4(SDHA):​c.1038C>G​(p.Ser346Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,646 control chromosomes in the GnomAD database, including 25,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S346S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (7548 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17940 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.935
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-233619-C-G is Benign according to our data. Variant chr5-233619-C-G is described in ClinVar as Benign. ClinVar VariationId is 130273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.935 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

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.1038C>G	p.Ser346Ser	synonymous	Exon 8 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.894C>G	p.Ser298Ser	synonymous	Exon 7 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.1038C>G	p.Ser346Ser	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.1038C>G	p.Ser346Ser	synonymous	Exon 8 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.1038C>G		non_coding_transcript_exon	Exon 8 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.1038C>G	p.Ser346Ser	synonymous	Exon 8 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37835 AN: 152008 Hom.: 7523 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.0820

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.155 AC: 39002 AN: 251450 AF XY: 0.145

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.0608

Gnomad FIN exome AF: 0.0861

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.138 AC: 201643 AN: 1461520 Hom.: 17940 Cov.: 32 AF XY: 0.135 AC XY: 98314 AN XY: 727096

African (AFR) AF: 0.573 AC: 19182 AN: 33456

American (AMR) AF: 0.190 AC: 8492 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4585 AN: 26130

East Asian (EAS) AF: 0.0480 AC: 1904 AN: 39692

South Asian (SAS) AF: 0.0902 AC: 7778 AN: 86246

European-Finnish (FIN) AF: 0.0883 AC: 4717 AN: 53394

Middle Eastern (MID) AF: 0.141 AC: 814 AN: 5766

European-Non Finnish (NFE) AF: 0.130 AC: 144627 AN: 1111754

Other (OTH) AF: 0.158 AC: 9544 AN: 60366

GnomAD4 genome AF: 0.249 AC: 37906 AN: 152126 Hom.: 7548 Cov.: 32 AF XY: 0.243 AC XY: 18079 AN XY: 74372

African (AFR) AF: 0.555 AC: 22993 AN: 41456

American (AMR) AF: 0.223 AC: 3406 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 612 AN: 3466

East Asian (EAS) AF: 0.0559 AC: 289 AN: 5170

South Asian (SAS) AF: 0.0886 AC: 427 AN: 4820

European-Finnish (FIN) AF: 0.0820 AC: 870 AN: 10612

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8468 AN: 68004

Other (OTH) AF: 0.237 AC: 501 AN: 2110

Alfa AF: 0.123 Hom.: 538

Bravo AF: 0.277

Asia WGS AF: 0.116 AC: 408 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.135

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (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	-0.54
CADD	Benign	4.0
DANN	Benign	0.46
PhyloP100		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs1041949; hg19: chr5-233734; COSMIC: COSV53765897; COSMIC: COSV53765897;