rs387906956

Positions:

• chr15-41394999-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000260361.9(NDUFAF1):​c.619A>C​(p.Thr207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NDUFAF1 ENST00000260361.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.68

Genes affected

NDUFAF1 (HGNC:18828): (NADH:ubiquinone oxidoreductase complex assembly factor 1) This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 15-41394999-T-G is Pathogenic according to our data. Variant chr15-41394999-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 30622.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF1	NM_016013.4	c.619A>C	p.Thr207Pro	missense_variant	3/5	ENST00000260361.9	NP_057097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFAF1	ENST00000260361.9	c.619A>C	p.Thr207Pro	missense_variant	3/5	1	NM_016013.4	ENSP00000260361	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 11, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.11	T;D
Sift4G	Benign	0.23	T;D
Polyphen		0.97	D;.
Vest4		0.88
MutPred		0.88		Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);
MVP		0.95
MPC		0.46
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.88

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: rs387906956; hg19: chr15-41687197;