5-254484-A-T

Variant names:

• chr5-254484-A-T
• rs6960
• NM_004168.4:c.1886A>T

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.1886A>T​(p.Tyr629Phe) variant causes a missense change. The variant allele was found at a frequency of 0.145 in 1,571,694 control chromosomes in the GnomAD database, including 22,863 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y629C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (6369 hom., cov: 28)
  • Exomes 𝑓: 0.14 (16494 hom.)
• Consequence: SDHA NM_004168.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.37
• Publications: 30 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 (MetaRNN=0.008063376).
• BP6: Variant 5-254484-A-T is Benign according to our data. Variant chr5-254484-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 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.1886A>T	p.Tyr629Phe	missense	Exon 14 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1742A>T	p.Tyr581Phe	missense	Exon 13 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1643A>T	p.Tyr548Phe	missense	Exon 12 of 13	NP_001317687.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1886A>T	p.Tyr629Phe	missense	Exon 14 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.*619A>T		non_coding_transcript_exon	Exon 13 of 24	ENSP00000499215.1
	ENSG00000286001	ENST00000651543.1		n.*619A>T		3_prime_UTR	Exon 13 of 24	ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35181 AN: 150204 Hom.: 6344 Cov.: 28

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.0806

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.143 AC: 23869 AN: 166952 AF XY: 0.136

Gnomad AFR exome AF: 0.532

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.0578

Gnomad FIN exome AF: 0.0839

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.135 AC: 192508 AN: 1421374 Hom.: 16494 Cov.: 32 AF XY: 0.133 AC XY: 93390 AN XY: 703670

African (AFR) AF: 0.539 AC: 17377 AN: 32234

American (AMR) AF: 0.186 AC: 7353 AN: 39568

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4137 AN: 25338

East Asian (EAS) AF: 0.0463 AC: 1777 AN: 38364

South Asian (SAS) AF: 0.0890 AC: 7234 AN: 81260

European-Finnish (FIN) AF: 0.0863 AC: 4389 AN: 50884

Middle Eastern (MID) AF: 0.151 AC: 619 AN: 4112

European-Non Finnish (NFE) AF: 0.129 AC: 140557 AN: 1090906

Other (OTH) AF: 0.154 AC: 9065 AN: 58708

GnomAD4 genome AF: 0.235 AC: 35251 AN: 150320 Hom.: 6369 Cov.: 28 AF XY: 0.228 AC XY: 16754 AN XY: 73434

African (AFR) AF: 0.515 AC: 20681 AN: 40150

American (AMR) AF: 0.217 AC: 3289 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3466

East Asian (EAS) AF: 0.0543 AC: 279 AN: 5136

South Asian (SAS) AF: 0.0857 AC: 411 AN: 4794

European-Finnish (FIN) AF: 0.0806 AC: 852 AN: 10574

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.123 AC: 8364 AN: 67756

Other (OTH) AF: 0.226 AC: 474 AN: 2094

Alfa AF: 0.102 Hom.: 225

ESP6500AA AF: 0.191 AC: 788

ESP6500EA AF: 0.0448 AC: 381

ExAC AF: 0.0895 AC: 10074

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	2	Pheochromocytoma/paraganglioma syndrome 5 (2)
-	-	1	Hereditary pheochromocytoma-paraganglioma (1)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex II deficiency, nuclear type 1 (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	0.072
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.4
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
MutPred		0.45		Loss of MoRF binding (P = 0.0726)
ClinPred		0.0098	T
GERP RS		2.9
Varity_R		0.34
Mutation Taster		=87/13	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: rs6960; hg19: chr5-254599; COSMIC: COSV53765955; COSMIC: COSV53765955;