rs1553996375

Variant names:

• chr5-218416-G-A
• rs1553996375
• NM_004168.4:c.61G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004168.4(SDHA):​c.61G>A​(p.Ala21Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004848
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.284
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06921834).
• BP6: Variant 5-218416-G-A is Benign according to our data. Variant chr5-218416-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472397.

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.61G>A	p.Ala21Thr	missense splice_region	Exon 1 of 15	NP_004159.2	P31040-1
	SDHA	NM_001294332.2		c.61G>A	p.Ala21Thr	missense splice_region	Exon 1 of 14	NP_001281261.1	P31040-2
	SDHA	NM_001330758.2		c.61G>A	p.Ala21Thr	missense splice_region	Exon 1 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.61G>A	p.Ala21Thr	missense splice_region	Exon 1 of 15	ENSP00000264932.6	P31040-1
	ENSG00000286001	ENST00000651543.1		n.61G>A		splice_region non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1	A0A494C1T6
	SDHA	ENST00000874235.1		c.61G>A	p.Ala21Thr	missense splice_region	Exon 1 of 16	ENSP00000544294.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1282928 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 632208

African (AFR) AF: 0.00 AC: 0 AN: 26084

American (AMR) AF: 0.00 AC: 0 AN: 20072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19302

East Asian (EAS) AF: 0.00 AC: 0 AN: 30178

South Asian (SAS) AF: 0.00 AC: 0 AN: 61854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036904

Other (OTH) AF: 0.00 AC: 0 AN: 52610

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (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
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.3
DANN	Benign	0.90
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.28
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.038
Sift	Benign	0.31	T
Sift4G	Benign	0.21	T
Polyphen		0.018	B
Vest4		0.13
MutPred		0.48		Loss of helix (P = 3e-04)
MVP		0.14
MPC		0.47
ClinPred		0.050	T
GERP RS		0.27
PromoterAI		0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.44
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0020
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: rs1553996375; hg19: chr5-218531;