chr5-224518-A-G

Variant names:

• chr5-224518-A-G
• rs1139424
• NM_004168.4:c.309A>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.309A>G​(p.Ala103Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,591,882 control chromosomes in the GnomAD database, including 19,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6846 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12173 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.652
• Publications: 19 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=-0.68).
• BP6: Variant 5-224518-A-G is Benign according to our data. Variant chr5-224518-A-G is described in ClinVar as Benign. ClinVar VariationId is 130280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.652 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 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.309A>G	p.Ala103Ala	synonymous	Exon 3 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.309A>G	p.Ala103Ala	synonymous	Exon 3 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.309A>G	p.Ala103Ala	synonymous	Exon 3 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.309A>G	p.Ala103Ala	synonymous	Exon 3 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.309A>G		non_coding_transcript_exon	Exon 3 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.309A>G	p.Ala103Ala	synonymous	Exon 3 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36481 AN: 152022 Hom.: 6820 Cov.: 33

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.150 AC: 37476 AN: 250446 AF XY: 0.141

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.0603

Gnomad FIN exome AF: 0.0856

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.128 AC: 184521 AN: 1439742 Hom.: 12173 Cov.: 32 AF XY: 0.126 AC XY: 90263 AN XY: 716870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.519 AC: 16785 AN: 32346

American (AMR) AF: 0.178 AC: 7842 AN: 44076

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4073 AN: 25874

East Asian (EAS) AF: 0.0471 AC: 1866 AN: 39640

South Asian (SAS) AF: 0.0867 AC: 7436 AN: 85718

European-Finnish (FIN) AF: 0.0878 AC: 4688 AN: 53368

Middle Eastern (MID) AF: 0.140 AC: 633 AN: 4512

European-Non Finnish (NFE) AF: 0.121 AC: 132398 AN: 1094712

Other (OTH) AF: 0.148 AC: 8800 AN: 59496

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.240 AC: 36552 AN: 152140 Hom.: 6846 Cov.: 33 AF XY: 0.235 AC XY: 17451 AN XY: 74390

African (AFR) AF: 0.524 AC: 21732 AN: 41440

American (AMR) AF: 0.220 AC: 3366 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 574 AN: 3468

East Asian (EAS) AF: 0.0558 AC: 289 AN: 5178

South Asian (SAS) AF: 0.0889 AC: 429 AN: 4824

European-Finnish (FIN) AF: 0.0821 AC: 871 AN: 10612

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8466 AN: 68010

Other (OTH) AF: 0.230 AC: 484 AN: 2108

Alfa AF: 0.181 Hom.: 1597

Bravo AF: 0.267

Asia WGS AF: 0.114 AC: 399 AN: 3478

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-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	-0.68
CADD	Benign	4.1
DANN	Benign	0.32
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=86/14	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: rs1139424; hg19: chr5-224633; COSMIC: COSV53765839; COSMIC: COSV53765839;