5-233457-A-G

Variant names:

• chr5-233457-A-G
• rs7710005
• NM_004168.4:c.896-20A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004168.4(SDHA):​c.896-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,610,802 control chromosomes in the GnomAD database, including 23,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6814 hom., cov: 33)
  • Exomes 𝑓: 0.14 (17149 hom.)
• Consequence: SDHA NM_004168.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.84
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-233457-A-G is Benign according to our data. Variant chr5-233457-A-G is described in ClinVar as Benign. ClinVar VariationId is 259249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	NM_004168.4	MANE Select	c.896-20A>G		intron	N/A	NP_004159.2
	SDHA	NM_001294332.2		c.752-20A>G		intron	N/A	NP_001281261.1
	SDHA	NM_001330758.2		c.896-20A>G		intron	N/A	NP_001317687.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.896-20A>G		intron	N/A	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.896-20A>G		intron	N/A	ENSP00000499215.1
	SDHA	ENST00000510361.5	TSL:2	c.752-20A>G		intron	N/A	ENSP00000427703.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36433 AN: 152102 Hom.: 6787 Cov.: 33

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.232

GnomAD2 exomes AF: 0.152 AC: 38298 AN: 251460 AF XY: 0.143

Gnomad AFR exome AF: 0.542

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0608

Gnomad FIN exome AF: 0.0862

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.136 AC: 198638 AN: 1458582 Hom.: 17149 Cov.: 30 AF XY: 0.134 AC XY: 96959 AN XY: 725802

African (AFR) AF: 0.539 AC: 17948 AN: 33312

American (AMR) AF: 0.189 AC: 8433 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4292 AN: 26104

East Asian (EAS) AF: 0.0480 AC: 1907 AN: 39694

South Asian (SAS) AF: 0.0899 AC: 7743 AN: 86168

European-Finnish (FIN) AF: 0.0884 AC: 4722 AN: 53390

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

European-Non Finnish (NFE) AF: 0.129 AC: 143469 AN: 1109178

Other (OTH) AF: 0.155 AC: 9327 AN: 60262

GnomAD4 genome AF: 0.240 AC: 36507 AN: 152220 Hom.: 6814 Cov.: 33 AF XY: 0.234 AC XY: 17416 AN XY: 74432

African (AFR) AF: 0.523 AC: 21674 AN: 41480

American (AMR) AF: 0.220 AC: 3366 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 574 AN: 3470

East Asian (EAS) AF: 0.0556 AC: 288 AN: 5184

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

European-Finnish (FIN) AF: 0.0823 AC: 874 AN: 10618

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8476 AN: 68022

Other (OTH) AF: 0.228 AC: 483 AN: 2114

Alfa AF: 0.184 Hom.: 1460

Bravo AF: 0.266

Asia WGS AF: 0.115 AC: 402 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	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.029
DANN	Benign	0.29
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7710005; hg19: chr5-233572; COSMIC: COSV53765885;