5-256399-G-C

Variant names:

• chr5-256399-G-C
• rs1042446
• NM_004168.4:c.1974G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004168.4(SDHA):​c.1974G>C​(p.Pro658Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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. P658P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.12
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-256399-G-C is Benign according to our data. Variant chr5-256399-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.

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.1974G>C	p.Pro658Pro	synonymous	Exon 15 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.1830G>C	p.Pro610Pro	synonymous	Exon 14 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.1731G>C	p.Pro577Pro	synonymous	Exon 13 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.1974G>C	p.Pro658Pro	synonymous	Exon 15 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.*707G>C		non_coding_transcript_exon	Exon 14 of 24	ENSP00000499215.1	A0A494C1T6
	ENSG00000286001	ENST00000651543.1		n.*707G>C		3_prime_UTR	Exon 14 of 24	ENSP00000499215.1	A0A494C1T6

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 293 AN: 141744 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00341

Gnomad AMI AF: 0.00230

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.000914

Gnomad EAS AF: 0.00104

Gnomad SAS AF: 0.00203

Gnomad FIN AF: 0.00258

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.00362

GnomAD2 exomes AF: 0.000239 AC: 57 AN: 238962 AF XY: 0.000162

Gnomad AFR exome AF: 0.00183

Gnomad AMR exome AF: 0.000338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000615

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00360 AC: 4311 AN: 1198342 Hom.: 1 Cov.: 32 AF XY: 0.00325 AC XY: 1955 AN XY: 601432

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

African (AFR) AF: 0.00484 AC: 139 AN: 28712

American (AMR) AF: 0.00295 AC: 115 AN: 38970

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 28 AN: 24158

East Asian (EAS) AF: 0.00101 AC: 36 AN: 35630

South Asian (SAS) AF: 0.000834 AC: 67 AN: 80340

European-Finnish (FIN) AF: 0.00134 AC: 64 AN: 47656

Middle Eastern (MID) AF: 0.00656 AC: 28 AN: 4268

European-Non Finnish (NFE) AF: 0.00414 AC: 3671 AN: 887152

Other (OTH) AF: 0.00317 AC: 163 AN: 51456

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00207 AC: 293 AN: 141854 Hom.: 0 Cov.: 33 AF XY: 0.00224 AC XY: 154 AN XY: 68834

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

African (AFR) AF: 0.00340 AC: 133 AN: 39112

American (AMR) AF: 0.00235 AC: 33 AN: 14038

Ashkenazi Jewish (ASJ) AF: 0.000914 AC: 3 AN: 3282

East Asian (EAS) AF: 0.00104 AC: 5 AN: 4818

South Asian (SAS) AF: 0.00203 AC: 9 AN: 4428

European-Finnish (FIN) AF: 0.00258 AC: 25 AN: 9708

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.00117 AC: 74 AN: 63356

Other (OTH) AF: 0.00358 AC: 7 AN: 1956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00206 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (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 and paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5 (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
-	-	1	SDHA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

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: rs1042446; hg19: chr5-256514; COSMIC: COSV53765147; COSMIC: COSV53765147;