rs863224198

Variant names:

• chr19-35995278-A-C
• rs863224198
• NM_001042631.3:c.4A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-35995278-A-C
• chr19-35995278-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001042631.3(SDHAF1):​c.4A>C​(p.Ser2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,383,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SDHAF1 NM_001042631.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.39
• 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29610366).

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.4A>C	p.Ser2Arg	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.4A>C	p.Ser2Arg	missense	Exon 1 of 1	ENSP00000368165.2	A6NFY7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000225 AC: 3 AN: 133352 AF XY: 0.0000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000913

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.0000130 AC: 18 AN: 1383992 Hom.: 0 Cov.: 29 AF XY: 0.0000117 AC XY: 8 AN XY: 683382

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.00 AC: 0 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.000111 AC: 4 AN: 36122

South Asian (SAS) AF: 0.00 AC: 0 AN: 79160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4438

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079024

Other (OTH) AF: 0.000242 AC: 14 AN: 57740

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.16	T
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.24		Loss of phosphorylation at S2 (P = 0.0146)
MVP		0.048
MPC		1.9
ClinPred		0.35	T
GERP RS		5.7
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.22
Mutation Taster		=63/37	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: rs863224198; hg19: chr19-36486180;