rs137853193

chr19-35995438-G-Achr19-35995438-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001042631.3(SDHAF1):c.164G>A(p.Arg55His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,354 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. R55P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHAF1 NM_001042631.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.21

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Interaction with SDHB (size 12) in uniprot entity SDHF1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001042631.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35995438-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 430.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHAF1	NM_001042631.3	c.164G>A	p.Arg55His	missense_variant	1/1	ENST00000378887.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHAF1	ENST00000378887.4	c.164G>A	p.Arg55His	missense_variant	1/1		NM_001042631.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000568 AC: 1 AN: 176190 Hom.: 0 AF XY: 0.0000101 AC XY: 1 AN XY: 98626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415354 Hom.: 0 Cov.: 30 AF XY: 0.00000285 AC XY: 2 AN XY: 702268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000907 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.62		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.51
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853193; hg19: chr19-36486340;