19-35995347-A-G

Variant names:

• chr19-35995347-A-G
• rs763030424
• NM_001042631.3:c.73A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001042631.3(SDHAF1):​c.73A>G​(p.Lys25Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K25Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SDHAF1 NM_001042631.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

SDHAF1 (HGNC:33867): (succinate dehydrogenase complex assembly factor 1) The succinate dehydrogenase (SDH) complex (or complex II) of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by this gene resides in the mitochondria, and is essential for SDH assembly, but does not physically associate with the complex in vivo. Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy (mitochondrial complex II deficiency).[provided by RefSeq, Mar 2010]

SDHAF1 Gene-Disease associations (from GenCC):

• mitochondrial complex 2 deficiency, nuclear type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.37914 (below the threshold of 3.09). Trascript score misZ: -2.4355 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex II deficiency, mitochondrial complex 2 deficiency, nuclear type 2, mitochondrial disease, Leigh syndrome, mitochondrial complex II deficiency, nuclear type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042631.3. 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
	SDHAF1	NM_001042631.3	MANE Select	c.73A>G	p.Lys25Glu	missense	Exon 1 of 1	NP_001036096.2	A6NFY7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHAF1	ENST00000378887.4	TSL:6 MANE Select	c.73A>G	p.Lys25Glu	missense	Exon 1 of 1	ENSP00000368165.2	A6NFY7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397988 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691492

African (AFR) AF: 0.00 AC: 0 AN: 32168

American (AMR) AF: 0.00 AC: 0 AN: 36998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 37214

South Asian (SAS) AF: 0.00 AC: 0 AN: 80624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4868

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087252

Other (OTH) AF: 0.0000172 AC: 1 AN: 58272

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
Vest4		0.68
MutPred		0.52		Loss of MoRF binding (P = 0.0056)
MVP		0.72
MPC		2.4
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		0.0081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.42
Mutation Taster		=74/26	polymorphism

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: rs763030424; hg19: chr19-36486249;