5-230996-T-C

Variant names:

• chr5-230996-T-C
• rs1126417
• NM_004168.4:c.891T>C

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.891T>C​(p.Pro297Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,613,450 control chromosomes in the GnomAD database, including 449,173 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. P297P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42249 hom., cov: 33)
  • Exomes 𝑓: 0.74 (406924 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 1.31
• Publications: 28 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, Labcorp Genetics (formerly Invitae), Illumina, G2P
• mitochondrial complex II deficiency, nuclear type 1

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 5-230996-T-C is Benign according to our data. Variant chr5-230996-T-C is described in ClinVar as Benign. ClinVar VariationId is 130283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 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.891T>C	p.Pro297Pro	synonymous	Exon 7 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.747T>C	p.Pro249Pro	synonymous	Exon 6 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.891T>C	p.Pro297Pro	synonymous	Exon 7 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.891T>C	p.Pro297Pro	synonymous	Exon 7 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.891T>C		non_coding_transcript_exon	Exon 7 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.891T>C	p.Pro297Pro	synonymous	Exon 7 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112600 AN: 152064 Hom.: 42215 Cov.: 33

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.737

GnomAD2 exomes AF: 0.700 AC: 175528 AN: 250646 AF XY: 0.703

Gnomad AFR exome AF: 0.786

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.757

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.742 AC: 1084235 AN: 1461266 Hom.: 406924 Cov.: 53 AF XY: 0.740 AC XY: 537674 AN XY: 726970

African (AFR) AF: 0.784 AC: 26226 AN: 33464

American (AMR) AF: 0.659 AC: 29439 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 18194 AN: 26128

East Asian (EAS) AF: 0.348 AC: 13821 AN: 39692

South Asian (SAS) AF: 0.683 AC: 58937 AN: 86240

European-Finnish (FIN) AF: 0.762 AC: 40672 AN: 53366

Middle Eastern (MID) AF: 0.626 AC: 3604 AN: 5760

European-Non Finnish (NFE) AF: 0.764 AC: 849774 AN: 1111552

Other (OTH) AF: 0.722 AC: 43568 AN: 60364

GnomAD4 genome AF: 0.741 AC: 112696 AN: 152184 Hom.: 42249 Cov.: 33 AF XY: 0.737 AC XY: 54854 AN XY: 74386

African (AFR) AF: 0.782 AC: 32477 AN: 41530

American (AMR) AF: 0.709 AC: 10840 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2443 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1740 AN: 5174

South Asian (SAS) AF: 0.674 AC: 3252 AN: 4826

European-Finnish (FIN) AF: 0.751 AC: 7959 AN: 10596

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51509 AN: 67992

Other (OTH) AF: 0.734 AC: 1546 AN: 2106

Alfa AF: 0.754 Hom.: 18873

Bravo AF: 0.735

Asia WGS AF: 0.523 AC: 1820 AN: 3478

EpiCase AF: 0.752

EpiControl AF: 0.747

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Mitochondrial complex II deficiency, nuclear type 1 (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Dilated cardiomyopathy 1GG (1)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	-	1	Neurodegeneration with ataxia and late-onset optic atrophy (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	9.8
DANN	Benign	0.37
PhyloP100		1.3
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: rs1126417; hg19: chr5-231111; COSMIC: COSV53767683; COSMIC: COSV53767683;