5-218356-A-T

Variant names:

• chr5-218356-A-T
• rs1061517
• NM_004168.4:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_004168.4(SDHA):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: SDHA NM_004168.4 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.636
• Publications: 28 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]

ENSG00000286001 (HGNC:):

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 61 pathogenic variants. Next in-frame start position is after 114 codons. Genomic position: 225446. Lost 0.170 part of the original CDS.
• PS1: Another start lost variant in NM_004168.4 (SDHA) was described as [Pathogenic] in ClinVar
• PP5: Variant 5-218356-A-T is Pathogenic according to our data. Variant chr5-218356-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 15	NP_004159.2
	SDHA	NM_001294332.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	NP_001281261.1
	SDHA	NM_001330758.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 13	NP_001317687.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHA	ENST00000264932.11	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 15	ENSP00000264932.6
	ENSG00000286001	ENST00000651543.1		n.1A>T		non_coding_transcript_exon	Exon 1 of 24	ENSP00000499215.1
	SDHA	ENST00000510361.5	TSL:2	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000427703.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000306 AC: 4 AN: 1308140 Hom.: 0 Cov.: 31 AF XY: 0.00000619 AC XY: 4 AN XY: 645810

African (AFR) AF: 0.00 AC: 0 AN: 26884

American (AMR) AF: 0.00 AC: 0 AN: 25114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20462

East Asian (EAS) AF: 0.00 AC: 0 AN: 31060

South Asian (SAS) AF: 0.0000151 AC: 1 AN: 66254

European-Finnish (FIN) AF: 0.0000294 AC: 1 AN: 33958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3694

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1047198

Other (OTH) AF: 0.00 AC: 0 AN: 53516

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	Pheochromocytoma/paraganglioma syndrome 5 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Neurodegeneration with ataxia and late-onset optic atrophy (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
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.92	T
PhyloP100		0.64
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.35
Sift	Benign	0.093	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.83
MutPred		0.99		Gain of loop (P = 0.2045)
MVP		0.69
ClinPred		0.74	D
GERP RS		2.5
PromoterAI		-0.54	Under-expression
Varity_R		0.32
gMVP		0.63
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1061517; hg19: chr5-218471;