NM_004168.4:c.1680G>A

Variant names:

• chr5-251354-G-A
• rs1139449
• NM_004168.4:c.1680G>A

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.1680G>A​(p.Thr560Thr) 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 1,609,722 control chromosomes in the GnomAD database, including 23,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T560T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (6843 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17064 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.40
• Publications: 6 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=-0.64).
• BP6: Variant 5-251354-G-A is Benign according to our data. Variant chr5-251354-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.39 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.1680G>A	p.Thr560Thr	synonymous	Exon 13 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1536G>A	p.Thr512Thr	synonymous	Exon 12 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1552-3039G>A		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.1680G>A	p.Thr560Thr	synonymous	Exon 13 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.*413G>A		non_coding_transcript_exon	Exon 12 of 24	ENSP00000499215.1
	ENSG00000286001	ENST00000651543.1		n.*413G>A		3_prime_UTR	Exon 12 of 24	ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36411 AN: 151798 Hom.: 6815 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0555

Gnomad SAS AF: 0.0880

Gnomad FIN AF: 0.0815

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.145 AC: 35830 AN: 246644 AF XY: 0.138

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.0586

Gnomad FIN exome AF: 0.0843

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.136 AC: 198179 AN: 1457808 Hom.: 17064 Cov.: 32 AF XY: 0.133 AC XY: 96663 AN XY: 725258

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

African (AFR) AF: 0.543 AC: 18026 AN: 33214

American (AMR) AF: 0.185 AC: 8221 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4284 AN: 26098

East Asian (EAS) AF: 0.0479 AC: 1900 AN: 39682

South Asian (SAS) AF: 0.0895 AC: 7706 AN: 86114

European-Finnish (FIN) AF: 0.0879 AC: 4689 AN: 53316

Middle Eastern (MID) AF: 0.137 AC: 776 AN: 5678

European-Non Finnish (NFE) AF: 0.129 AC: 143260 AN: 1109132

Other (OTH) AF: 0.155 AC: 9317 AN: 60202

⚠️ 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: 36484 AN: 151914 Hom.: 6843 Cov.: 32 AF XY: 0.234 AC XY: 17388 AN XY: 74240

African (AFR) AF: 0.525 AC: 21715 AN: 41332

American (AMR) AF: 0.220 AC: 3356 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3466

East Asian (EAS) AF: 0.0550 AC: 285 AN: 5178

South Asian (SAS) AF: 0.0882 AC: 425 AN: 4816

European-Finnish (FIN) AF: 0.0815 AC: 864 AN: 10602

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.124 AC: 8447 AN: 67940

Other (OTH) AF: 0.229 AC: 483 AN: 2106

Alfa AF: 0.157 Hom.: 902

Bravo AF: 0.267

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.64
CADD	Benign	4.5
DANN	Benign	0.71
PhyloP100		-1.4
PromoterAI		0.0036	Neutral
Mutation Taster		=100/0	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: rs1139449; hg19: chr5-251469; COSMIC: COSV53765937;