chr6-96889661-C-T

Variant names:

• chr6-96889661-C-T
• rs7758762
• NM_014165.4:c.*1443G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014165.4(NDUFAF4):​c.*1443G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,376 control chromosomes in the GnomAD database, including 4,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4532 hom., cov: 32)
  • Exomes 𝑓: 0.18 (3 hom.)
• Consequence: NDUFAF4 NM_014165.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.475
• Publications: 4 publications found

Genes affected

NDUFAF4 (HGNC:21034): (NADH:ubiquinone oxidoreductase complex assembly factor 4) NADH:ubiquinone oxidoreductase (complex I) 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. This gene encodes a complex I assembly factor. Mutations in this gene are a cause of mitochondrial complex I deficiency. [provided by RefSeq, Oct 2009]

NDUFAF4 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 15

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-96889661-C-T is Benign according to our data. Variant chr6-96889661-C-T is described in ClinVar as Benign. ClinVar VariationId is 358249.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014165.4. 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
	NDUFAF4	NM_014165.4	MANE Select	c.*1443G>A		3_prime_UTR	Exon 3 of 3	NP_054884.1	Q9P032

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF4	ENST00000316149.8	TSL:1 MANE Select	c.*1443G>A		3_prime_UTR	Exon 3 of 3	ENSP00000358272.4	Q9P032
	NDUFAF4	ENST00000926051.1		c.*1443G>A		3_prime_UTR	Exon 3 of 3	ENSP00000596110.1
	NDUFAF4	ENST00000872119.1		c.*1443G>A		3_prime_UTR	Exon 3 of 3	ENSP00000542178.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36703 AN: 151854 Hom.: 4530 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.185 AC: 75 AN: 406 Hom.: 3 Cov.: 0 AF XY: 0.179 AC XY: 44 AN XY: 246

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.185 AC: 74 AN: 400

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.242 AC: 36720 AN: 151970 Hom.: 4532 Cov.: 32 AF XY: 0.243 AC XY: 18037 AN XY: 74272

African (AFR) AF: 0.229 AC: 9486 AN: 41446

American (AMR) AF: 0.327 AC: 4995 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 584 AN: 3464

East Asian (EAS) AF: 0.347 AC: 1788 AN: 5160

South Asian (SAS) AF: 0.255 AC: 1227 AN: 4812

European-Finnish (FIN) AF: 0.224 AC: 2360 AN: 10554

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15433 AN: 67946

Other (OTH) AF: 0.239 AC: 505 AN: 2116

Alfa AF: 0.232 Hom.: 790

Bravo AF: 0.251

Asia WGS AF: 0.315 AC: 1096 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.72
PhyloP100		-0.47
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: rs7758762; hg19: chr6-97337537; COSMIC: COSV60214220; COSMIC: COSV60214220;