chr17-81241219-C-T

Variant names:

• chr17-81241219-C-T
• rs112417848
• NM_001086521.2:c.*203C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001086521.2(NDUFAF8):​c.*203C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,352,812 control chromosomes in the GnomAD database, including 972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (78 hom., cov: 32)
  • Exomes 𝑓: 0.036 (894 hom.)
• Consequence: NDUFAF8 NM_001086521.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.48
• Publications: 4 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=-0.91).
• BP6: Variant 17-81241219-C-T is Benign according to our data. Variant chr17-81241219-C-T is described in ClinVar as Benign. ClinVar VariationId is 1225139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0278 (4224/152168) while in subpopulation NFE AF = 0.037 (2514/67996). AF 95% confidence interval is 0.0358. There are 78 homozygotes in GnomAd4. There are 2156 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 AR gene

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.*203C>T		3_prime_UTR	Exon 3 of 3	NP_001079990.1	A1L188
	NDUFAF8	NM_001353402.1		c.*66C>T		3_prime_UTR	Exon 3 of 3	NP_001340331.1
	NDUFAF8	NM_001353403.1		c.*66C>T		3_prime_UTR	Exon 3 of 3	NP_001340332.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.*203C>T		3_prime_UTR	Exon 3 of 3	ENSP00000400184.2	A1L188
	NDUFAF8	ENST00000576002.1	TSL:2	c.*66C>T		3_prime_UTR	Exon 2 of 2	ENSP00000461155.1	I3L4C8
	NDUFAF8	ENST00000577158.2	TSL:1	n.*138C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4225 AN: 152050 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0340

GnomAD4 exome AF: 0.0355 AC: 42650 AN: 1200644 Hom.: 894 Cov.: 20 AF XY: 0.0354 AC XY: 20494 AN XY: 578612

African (AFR) AF: 0.00776 AC: 208 AN: 26816

American (AMR) AF: 0.0252 AC: 435 AN: 17252

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 1461 AN: 17216

East Asian (EAS) AF: 0.000124 AC: 4 AN: 32298

South Asian (SAS) AF: 0.0193 AC: 972 AN: 50234

European-Finnish (FIN) AF: 0.0510 AC: 1376 AN: 26972

Middle Eastern (MID) AF: 0.0535 AC: 177 AN: 3308

European-Non Finnish (NFE) AF: 0.0372 AC: 36315 AN: 977056

Other (OTH) AF: 0.0344 AC: 1702 AN: 49492

GnomAD4 genome AF: 0.0278 AC: 4224 AN: 152168 Hom.: 78 Cov.: 32 AF XY: 0.0290 AC XY: 2156 AN XY: 74372

African (AFR) AF: 0.00686 AC: 285 AN: 41524

American (AMR) AF: 0.0224 AC: 343 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0850 AC: 295 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0186 AC: 90 AN: 4826

European-Finnish (FIN) AF: 0.0525 AC: 555 AN: 10570

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2514 AN: 67996

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.0345 Hom.: 30

Bravo AF: 0.0258

Asia WGS AF: 0.00664 AC: 23 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	-0.91
CADD	Benign	0.24
DANN	Benign	0.65
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs112417848; hg19: chr17-79215019;