rs3204853

Variant names:

• chr15-41396968-C-A
• rs3204853
• NM_016013.4:c.92G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-41396968-C-A
• chr15-41396968-C-G
• chr15-41396968-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_016013.4(NDUFAF1):​c.92G>T​(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,611,294 control chromosomes in the GnomAD database, including 47,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (3397 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44148 hom.)
• Consequence: NDUFAF1 NM_016013.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.815
• Publications: 46 publications found

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]

NDUFAF1 Gene-Disease associations (from GenCC):

• mitochondrial disease

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 11

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-41396968-C-A is Benign according to our data. Variant chr15-41396968-C-A is described in ClinVar as Benign. ClinVar VariationId is 129689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016013.4. 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
	NDUFAF1	NM_016013.4	MANE Select	c.92G>T	p.Arg31Leu	missense	Exon 2 of 5	NP_057097.2
	NDUFAF1	NM_001437486.1		c.92G>T	p.Arg31Leu	missense	Exon 2 of 5	NP_001424415.1
	NDUFAF1	NM_001437487.1		c.92G>T	p.Arg31Leu	missense	Exon 2 of 5	NP_001424416.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.92G>T	p.Arg31Leu	missense	Exon 2 of 5	ENSP00000260361.4
	NDUFAF1	ENST00000559127.5	TSL:1	n.92G>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000453027.1
	NDUFAF1	ENST00000853315.1		c.92G>T	p.Arg31Leu	missense	Exon 1 of 5	ENSP00000523374.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28163 AN: 151822 Hom.: 3399 Cov.: 31

Gnomad AFR AF: 0.0489

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.202 AC: 50286 AN: 249374 AF XY: 0.208

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.238 AC: 347596 AN: 1459354 Hom.: 44148 Cov.: 34 AF XY: 0.238 AC XY: 172591 AN XY: 725852

African (AFR) AF: 0.0434 AC: 1445 AN: 33322

American (AMR) AF: 0.135 AC: 5951 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 6748 AN: 26026

East Asian (EAS) AF: 0.0153 AC: 606 AN: 39684

South Asian (SAS) AF: 0.189 AC: 16291 AN: 86078

European-Finnish (FIN) AF: 0.299 AC: 15938 AN: 53374

Middle Eastern (MID) AF: 0.225 AC: 1291 AN: 5750

European-Non Finnish (NFE) AF: 0.257 AC: 285895 AN: 1110670

Other (OTH) AF: 0.223 AC: 13431 AN: 60242

GnomAD4 genome AF: 0.185 AC: 28154 AN: 151940 Hom.: 3397 Cov.: 31 AF XY: 0.187 AC XY: 13878 AN XY: 74224

African (AFR) AF: 0.0488 AC: 2022 AN: 41464

American (AMR) AF: 0.180 AC: 2737 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 896 AN: 3470

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5174

South Asian (SAS) AF: 0.177 AC: 852 AN: 4804

European-Finnish (FIN) AF: 0.303 AC: 3190 AN: 10520

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17619 AN: 67974

Other (OTH) AF: 0.191 AC: 402 AN: 2100

Alfa AF: 0.229 Hom.: 15515

Bravo AF: 0.171

TwinsUK AF: 0.244 AC: 903

ALSPAC AF: 0.257 AC: 990

ESP6500AA AF: 0.0506 AC: 223

ESP6500EA AF: 0.261 AC: 2242

ExAC AF: 0.199 AC: 24191

EpiCase AF: 0.257

EpiControl AF: 0.257

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 11 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.9
DANN	Benign	0.47
DEOGEN2	Benign	0.00098	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.81
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.026
Sift	Benign	0.15	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.093
ClinPred		0.0027	T
GERP RS		-4.1
Varity_R		0.040
gMVP		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3204853; hg19: chr15-41689166; COSMIC: COSV52974941;