17-81240922-A-G

Variant names:

• chr17-81240922-A-G
• rs59124084
• NM_001086521.2:c.196-65A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001086521.2(NDUFAF8):​c.196-65A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,565,888 control chromosomes in the GnomAD database, including 1,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (554 hom., cov: 32)
  • Exomes 𝑓: 0.017 (631 hom.)
• Consequence: NDUFAF8 NM_001086521.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-81240922-A-G is Benign according to our data. Variant chr17-81240922-A-G is described in ClinVar as Benign. ClinVar VariationId is 1238158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001086521.2. 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.196-65A>G		intron	N/A	NP_001079990.1	A1L188
	NDUFAF8	NM_001353402.1		c.200-65A>G		intron	N/A	NP_001340331.1
	NDUFAF8	NM_001353403.1		c.38-65A>G		intron	N/A	NP_001340332.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.196-65A>G		intron	N/A	ENSP00000400184.2	A1L188
	NDUFAF8	ENST00000577158.2	TSL:1	n.184-65A>G		intron	N/A
	NDUFAF8	ENST00000576002.1	TSL:2	c.71-65A>G		intron	N/A	ENSP00000461155.1	I3L4C8

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8367 AN: 152164 Hom.: 553 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0449

GnomAD4 exome AF: 0.0170 AC: 24042 AN: 1413606 Hom.: 631 AF XY: 0.0165 AC XY: 11595 AN XY: 702394

African (AFR) AF: 0.168 AC: 5435 AN: 32320

American (AMR) AF: 0.0155 AC: 630 AN: 40750

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 324 AN: 25210

East Asian (EAS) AF: 0.0000776 AC: 3 AN: 38666

South Asian (SAS) AF: 0.00916 AC: 750 AN: 81840

European-Finnish (FIN) AF: 0.00586 AC: 302 AN: 51556

Middle Eastern (MID) AF: 0.0466 AC: 264 AN: 5662

European-Non Finnish (NFE) AF: 0.0139 AC: 14981 AN: 1078920

Other (OTH) AF: 0.0231 AC: 1353 AN: 58682

GnomAD4 genome AF: 0.0550 AC: 8378 AN: 152282 Hom.: 554 Cov.: 32 AF XY: 0.0533 AC XY: 3970 AN XY: 74476

African (AFR) AF: 0.163 AC: 6788 AN: 41530

American (AMR) AF: 0.0221 AC: 338 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4832

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 999 AN: 68030

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0540 Hom.: 75

Bravo AF: 0.0613

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.024
DANN	Benign	0.58
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs59124084; hg19: chr17-79214722;