ENST00000647561:c.-74T>C

Variant names:

• chr11-67606931-T-C
• rs373383800
• ENST00000647561.1:c.-74T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000647561.1(NDUFV1):​c.-74T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,509,580 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: NDUFV1 ENST00000647561.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.344
• Publications: 0 publications found

Genes affected

NDUFV1 (HGNC:7716): (NADH:ubiquinone oxidoreductase core subunit V1) The mitochondrial respiratory chain provides energy to cells via oxidative phosphorylation and consists of four membrane-bound electron-transporting protein complexes (I-IV) and an ATP synthase (complex V). This gene encodes a 51 kDa subunit of the NADH:ubiquinone oxidoreductase complex I; a large complex with at least 45 nuclear and mitochondrial encoded subunits that liberates electrons from NADH and channels them to ubiquinone. This subunit carries the NADH-binding site as well as flavin mononucleotide (FMN)- and Fe-S-biding sites. Defects in complex I are a common cause of mitochondrial dysfunction; a syndrome that occurs in approximately 1 in 10,000 live births. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

NDUFV1-DT (HGNC:26915): (NDUFV1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-67606931-T-C is Benign according to our data. Variant chr11-67606931-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 877316.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00673 (1024/152188) while in subpopulation AFR AF = 0.0232 (965/41534). AF 95% confidence interval is 0.022. There are 11 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647561.1. 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
	NDUFV1	NM_007103.4	MANE Select	c.-74T>C		upstream_gene	N/A	NP_009034.2
	NDUFV1	NM_001166102.2		c.-74T>C		upstream_gene	N/A	NP_001159574.1	P49821-2
	NDUFV1-DT	NR_130935.1		n.-225A>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFV1	ENST00000647561.1		c.-74T>C		5_prime_UTR	Exon 2 of 11	ENSP00000497587.1	P49821-1
	NDUFV1	ENST00000926237.1		c.-74T>C		5_prime_UTR	Exon 1 of 10	ENSP00000596296.1
	NDUFV1	ENST00000926238.1		c.-74T>C		5_prime_UTR	Exon 1 of 10	ENSP00000596297.1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1022 AN: 152070 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.000690 AC: 936 AN: 1357392 Hom.: 11 Cov.: 23 AF XY: 0.000615 AC XY: 414 AN XY: 673626

African (AFR) AF: 0.0219 AC: 687 AN: 31342

American (AMR) AF: 0.00139 AC: 51 AN: 36564

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24910

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36836

South Asian (SAS) AF: 0.000971 AC: 77 AN: 79278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48216

Middle Eastern (MID) AF: 0.000539 AC: 3 AN: 5566

European-Non Finnish (NFE) AF: 0.0000299 AC: 31 AN: 1038018

Other (OTH) AF: 0.00150 AC: 85 AN: 56662

GnomAD4 genome AF: 0.00673 AC: 1024 AN: 152188 Hom.: 11 Cov.: 32 AF XY: 0.00657 AC XY: 489 AN XY: 74400

African (AFR) AF: 0.0232 AC: 965 AN: 41534

American (AMR) AF: 0.00314 AC: 48 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00485 Hom.: 0

Bravo AF: 0.00769

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.63
PhyloP100		0.34
PromoterAI		0.063	Neutral
Mutation Taster		=300/0	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: rs373383800; hg19: chr11-67374402;