rs13070

Variant names:

• chr5-251426-A-G
• rs13070
• NM_004168.4:c.1752A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-251426-A-G
• chr5-251426-A-T

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.1752A>G​(p.Ala584Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,612,340 control chromosomes in the GnomAD database, including 24,109 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. A584A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (6866 hom., cov: 33)
  • Exomes 𝑓: 0.14 (17243 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.447
• Publications: 8 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: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Ambry Genetics, ClinGen
• 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=-0.75).
• BP6: Variant 5-251426-A-G is Benign according to our data. Variant chr5-251426-A-G is described in ClinVar as Benign. ClinVar VariationId is 130277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.447 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 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.1752A>G	p.Ala584Ala	synonymous	Exon 13 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1608A>G	p.Ala536Ala	synonymous	Exon 12 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1552-2967A>G		intron	N/A	NP_001317687.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1752A>G	p.Ala584Ala	synonymous	Exon 13 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.*485A>G		non_coding_transcript_exon	Exon 12 of 24	ENSP00000499215.1
	ENSG00000286001	ENST00000651543.1		n.*485A>G		3_prime_UTR	Exon 12 of 24	ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36504 AN: 151962 Hom.: 6838 Cov.: 33

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0561

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.151 AC: 37847 AN: 250352 AF XY: 0.142

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.0858

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.137 AC: 199524 AN: 1460260 Hom.: 17243 Cov.: 32 AF XY: 0.134 AC XY: 97380 AN XY: 726562

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

African (AFR) AF: 0.544 AC: 18104 AN: 33292

American (AMR) AF: 0.188 AC: 8375 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4296 AN: 26112

East Asian (EAS) AF: 0.0480 AC: 1905 AN: 39690

South Asian (SAS) AF: 0.0902 AC: 7773 AN: 86194

European-Finnish (FIN) AF: 0.0884 AC: 4719 AN: 53392

Middle Eastern (MID) AF: 0.138 AC: 797 AN: 5758

European-Non Finnish (NFE) AF: 0.130 AC: 144189 AN: 1110904

Other (OTH) AF: 0.155 AC: 9366 AN: 60286

⚠️ 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: 0.241 AC: 36578 AN: 152080 Hom.: 6866 Cov.: 33 AF XY: 0.235 AC XY: 17459 AN XY: 74356

African (AFR) AF: 0.526 AC: 21764 AN: 41410

American (AMR) AF: 0.220 AC: 3364 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 574 AN: 3472

East Asian (EAS) AF: 0.0556 AC: 288 AN: 5178

South Asian (SAS) AF: 0.0891 AC: 430 AN: 4824

European-Finnish (FIN) AF: 0.0817 AC: 866 AN: 10602

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

European-Non Finnish (NFE) AF: 0.125 AC: 8467 AN: 67984

Other (OTH) AF: 0.229 AC: 484 AN: 2112

Alfa AF: 0.182 Hom.: 1673

Bravo AF: 0.268

Asia WGS AF: 0.114 AC: 400 AN: 3478

ClinVar

ClinVar submissions as Germline

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	Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	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	-0.75
CADD	Benign	1.6
DANN	Benign	0.47
PhyloP100		-0.45
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	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: rs13070; hg19: chr5-251541; COSMIC: COSV53765948; COSMIC: COSV53765948;