11-67607007-G-T

Variant names:

• chr11-67607007-G-T
• NM_007103.4:c.3G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_007103.4(NDUFV1):​c.3G>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDUFV1 NM_007103.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.44

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 102 codons. Genomic position: 67608700. Lost 0.218 part of the original CDS.
• PS1: Another start lost variant in NM_007103.4 (NDUFV1) was described as [Likely_pathogenic] in ClinVar as 3600151
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-67607007-G-T is Pathogenic according to our data. Variant chr11-67607007-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3600152.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV1	NM_007103.4	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	ENST00000322776.11	NP_009034.2
NDUFV1	NM_001166102.2	c.3G>T	p.Met1?	start_lost	Exon 1 of 10		NP_001159574.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV1	ENST00000322776.11	c.3G>T	p.Met1?	start_lost	Exon 1 of 10	1	NM_007103.4	ENSP00000322450.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458690 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725482

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 4 Pathogenic:1

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;.;T;.;T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
PROVEAN	Benign	-0.25	.;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.017	.;D;T;T;D;T
Sift4G	Uncertain	0.032	.;D;T;T;D;T
Polyphen		0.0030	B;B;B;B;.;.
Vest4		0.86, 0.67, 0.88
MutPred		0.91		Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);
MVP		0.89
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.76
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-67374478;