17-81239382-G-A

Variant names:

• chr17-81239382-G-A
• rs1007712101
• NM_001086521.2:c.19G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001353403.1(NDUFAF8):​c.-405G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000821 in 1,218,188 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: NDUFAF8 NM_001353403.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

Genes affected

NDUFAF8 (HGNC:33551): (NADH:ubiquinone oxidoreductase complex assembly factor 8) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Implicated in nuclear type mitochondrial complex I deficiency 34. [provided by Alliance of Genome Resources, Apr 2022]

NDUFAF8 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 34

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353403.1. 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
	NDUFAF8	NM_001086521.2	MANE Select	c.19G>A	p.Val7Met	missense	Exon 1 of 3	NP_001079990.1	A1L188
	NDUFAF8	NM_001353403.1		c.-405G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001340332.1
	NDUFAF8	NM_001353402.1		c.19G>A	p.Val7Met	missense	Exon 1 of 3	NP_001340331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.19G>A	p.Val7Met	missense	Exon 1 of 3	ENSP00000400184.2	A1L188
	NDUFAF8	ENST00000577158.2	TSL:1	n.78G>A		non_coding_transcript_exon	Exon 1 of 3
	NDUFAF8	ENST00000573090.1	TSL:3	n.72G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.21e-7 AC: 1 AN: 1218188 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 587358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23488

American (AMR) AF: 0.00 AC: 0 AN: 9790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16722

East Asian (EAS) AF: 0.00 AC: 0 AN: 27336

South Asian (SAS) AF: 0.0000194 AC: 1 AN: 51522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3370

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 993410

Other (OTH) AF: 0.00 AC: 0 AN: 49748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.35	T
PhyloP100		2.0
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.40
MutPred		0.31		Gain of disorder (P = 0.0251)
MVP		0.061
MPC		0.67
ClinPred		0.87	D
GERP RS		3.8
PromoterAI		-0.0055	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.21
gMVP		0.55

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: rs1007712101; hg19: chr17-79213182;