chr5-230865-A-G

Variant names:

• chr5-230865-A-G
• rs2288461
• NM_004168.4:c.771-11A>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.771-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,613,942 control chromosomes in the GnomAD database, including 633,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62026 hom., cov: 31)
  • Exomes 𝑓: 0.88 (571660 hom.)
• Consequence: SDHA NM_004168.4 intron
• Scores: Splicing: ADA: 0.00001184
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.249
• Publications: 13 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=-0.84).
• BP6: Variant 5-230865-A-G is Benign according to our data. Variant chr5-230865-A-G is described in ClinVar as Benign. ClinVar VariationId is 259248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 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.771-11A>G		intron	N/A	NP_004159.2
	SDHA	NM_001294332.2		c.627-11A>G		intron	N/A	NP_001281261.1
	SDHA	NM_001330758.2		c.771-11A>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.771-11A>G		intron	N/A	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.771-11A>G		intron	N/A	ENSP00000499215.1
	SDHA	ENST00000874235.1		c.771-11A>G		intron	N/A	ENSP00000544294.1

Frequencies

GnomAD3 genomes AF: 0.900 AC: 136939 AN: 152070 Hom.: 61966 Cov.: 31

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.917

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.880

Gnomad OTH AF: 0.893

GnomAD2 exomes AF: 0.877 AC: 220444 AN: 251370 AF XY: 0.877

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.812

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.923

Gnomad NFE exome AF: 0.884

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.883 AC: 1291092 AN: 1461754 Hom.: 571660 Cov.: 57 AF XY: 0.883 AC XY: 641980 AN XY: 727182

African (AFR) AF: 0.972 AC: 32551 AN: 33480

American (AMR) AF: 0.892 AC: 39872 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 21104 AN: 26132

East Asian (EAS) AF: 0.680 AC: 27006 AN: 39696

South Asian (SAS) AF: 0.901 AC: 77719 AN: 86256

European-Finnish (FIN) AF: 0.920 AC: 49139 AN: 53404

Middle Eastern (MID) AF: 0.783 AC: 4511 AN: 5764

European-Non Finnish (NFE) AF: 0.887 AC: 986468 AN: 1111916

Other (OTH) AF: 0.873 AC: 52722 AN: 60386

GnomAD4 genome AF: 0.901 AC: 137060 AN: 152188 Hom.: 62026 Cov.: 31 AF XY: 0.902 AC XY: 67102 AN XY: 74422

African (AFR) AF: 0.970 AC: 40305 AN: 41542

American (AMR) AF: 0.893 AC: 13649 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 2802 AN: 3470

East Asian (EAS) AF: 0.662 AC: 3405 AN: 5140

South Asian (SAS) AF: 0.894 AC: 4314 AN: 4826

European-Finnish (FIN) AF: 0.922 AC: 9780 AN: 10606

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.880 AC: 59864 AN: 67998

Other (OTH) AF: 0.891 AC: 1879 AN: 2108

Alfa AF: 0.911 Hom.: 29721

Bravo AF: 0.899

Asia WGS AF: 0.785 AC: 2731 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.8
DANN	Benign	0.31
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2288461; hg19: chr5-230980; COSMIC: COSV53768388; COSMIC: COSV53768388;